Diacylglycerol Acyltransferase Inhibitors

ABSTRACT

Provided herein are compounds of the formula (I): 
     
       
         
         
             
             
         
       
     
     as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, obesity, type II diabetes mellitus and metabolic syndrome.

PRIORITY TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/740,578, filed Nov. 28, 2005, and U.S. Provisional Application No.60/849,352, filed Oct. 4, 2006, which are hereby incorporated byreference in their entirety.

FIELD OF THE INVENTION

The invention relates to inhibitors of diacylglycerol acyltransferase.The inhibitors include, for example, oxazoles, and are useful for thetreatment of diseases such as obesity, type II diabetes mellitus,dyslipidemia and metabolic syndrome.

All documents cited or relied upon below are expressly incorporatedherein by reference.

BACKGROUND OF THE INVENTION

Triglycerides or triacylglycerols are the major form of energy storagein eukaryotic organisms. In mammals, these compounds are primarilysynthesized in three tissues: the small intestine, liver, andadipocytes. Triglycerides or triacylglycerols support the majorfunctions of dietary fat absorption, packaging of newly synthesizedfatty acids and storage in fat tissue (see Subauste and Burant, CurrentDrug Targets—Immune, Endocrine & Metabolic Disorders (2003) 3, 263-270).

Diacylglycerol O-acyltransferase, also known as diglycerideacyltransferase or DGAT, is a key enzyme in triglyceride synthesis. DGATcatalyzes the final and rate-limiting step in triacylglycerol synthesisfrom 1,2-diacylglycerol (DAG) and long chain fatty acyl CoA assubstrates. Thus, DGAT plays an essential role in the metabolism ofcellular diacylglycerol and is critically important for triglycerideproduction and energy storage homeostasis (see Mayorek et al, EuropeanJournal of Biochemistry (1989) 182, 395-400).

DGAT has a specificity for sn-1,2 diacylglycerols and will accept a widevariety of fatty acyl chain lengths (see Farese et al, Current Opinionsin Lipidology (2000) 11, 229-234). DGAT activity levels increase in fatcells as they differentiate in vitro and recent evidence suggests thatDGAT may be regulated in adipose tissue post-transcriptionally (seeColeman et al, Journal of Molecular Biology (1978) 253, 7256-7261 and Yuet al, Journal of Molecular Biology (2002) 277, 50876-50884). DGATactivity is primarily expressed in the endoplasmic reticulum (seeColman, Methods in Enzymology (1992) 209, 98-104). In hepatocytes, DGATactivity has been shown to be expressed on both the cytosolic andluminal surfaces of the endoplasmic reticular membrane (see Owen et al,Biochemical Journal (1997) 323 (pt 1), 17-21 and Waterman et al, Journalof Lipid Research (2002) 43, 1555-156). In the liver, the regulation oftriglyceride synthesis and partitioning, between retention as cytosolicdroplets and secretion, is of primary importance in determining the rateof VLDL production (see Shelness and Sellers, Current Opinions inLipidology (2001) 12, 151-157 and Owen et al, Biochemical Journal (1997)323 (pt 1), 17-21).

Two forms of DGAT have been cloned and are designated DGAT1 and DGAT2(see Cases et al, Proceedings of the National Academy of Science, USA(1998) 95, 13018-13023, Lardizabal et al, Journal of BiologicalChemistry (2001) 276, 38862-38869 and Cases et al, Journal of BiologicalChemistry (2001) 276, 38870-38876). Although both enzymes utilize thesame substrates, there is no homology between DGAT1 and DGAT2. Bothenzymes are widely expressed however some differences do exist in therelative abundance of expression in various tissues.

The gene encoding mouse DGAT1 has been used to create DGAT knock-out.These mice, although unable to express a functional DGAT enzyme (Dgat−/−mice), are viable and continue to synthesize triglycerides (see Smith etal, Nature Genetics (2000) 25, 87-90). This would suggest that multiplecatalytic mechanisms contribute to triglyceride synthesis, such asDGAT2. An alternative pathway has also been shown to form triglyceridesfrom two diacylglycerols by the action of diacylglycerol transacylase(see Lehner and Kuksis, Progress in Lipid Research (1996) 35, 169-210).

Dgat−/− mice are resistant to diet-induced obesity and remain lean. Whenfed a high fat diet, Dgat−/− mice maintain weights comparable to micefed a diet with regular fat content. Dgat−/− mice have lower tissuetriglyceride levels. The resistance to weight gain seen in the knockoutmice, which have a slightly higher food intake, is due to an increasedenergy expenditure and increased sensitivity to insulin and leptin (seeSmith et al, Nature Genetics (2000) 25, 87-90, Chen and Farese, Trendsin Cardiovascular Medicine (2000) 10, 188-192, Chen and Farese, CurrentOpinions in Clinical Nutrition and Metabolic Care (2002) 5, 359-363 andChen et al, Journal of Clinical Investigation (2002) 109, 1049-1055).Dgat−/− mice have reduced rates of triglyceride absorption, improvedtriglyceride metabolism, and improved glucose metabolism, with lowerglucose and insulin levels following a glucose load, in comparison towild-type mice (see Buhman et al, Journal of Biological Chemistry (2002)277, 25474-25479 and Chen and Farese, Trends in Cardiovascular Medicine(2000) 10, 188-192).

Disorders or imbalances in triglyceride metabolism, both absorption aswell as de novo synthesis, have been implicated in the pathogenesis of avariety of disease risks These include obesity, insulin resistancesyndrome, type II diabetes, dyslipidemia, metabolic syndrome (syndromeX) and coronary heart disease (see Kahn, Nature Genetics (2000) 25, 6-7,Yanovski and Yanovski, New England Journal of Medicine (2002) 346,591-602, Lewis et al, Endocrine Reviews (2002) 23, 201, Brazil, NatureReviews Drug Discovery (2002) 1, 408, Malloy and Kane, Advances inInternal Medicine (2001) 47, 111, Subauste and Burant, Current DrugTargets—Immune, Endocrine & Metabolic Disorders (2003) 3, 263-270 and Yuand Ginsberg, Annals of Medicine (2004) 36, 252-261). Compounds that candecrease the synthesis of triglycerides from diacylglycerol byinhibiting or lowering the activity of the DGAT enzyme would be of valueas therapeutic agents for the treatment diseases associated withabnormal metabolism of triglycerides.

Known inhibitors of DGAT include: dibenzoxazepinones (see Ramharack, etal, EP1219716 and Burrows et al, 26^(th) National Medicinal ChemistrySymposium (1998) poster C-22), substituted amino-pyrimidino-oxazines(see Fox et al, WO2004047755), chalcones such as xanthohumol (see Tabataet al, Phytochemistry (1997) 46, 683-687 and Casaschi et al, Journal ofNutrition (2004) 134, 1340-1346), substituted benzyl-phosphonates (seeKurogi et al, Journal of Medicinal Chemistry (1996) 39, 1433-1437, Goto,et al, Chemistry and Pharmaceutical Bulletin (1996) 44, 547-551, Ikeda,et al, Thirteenth International Symposium on Athersclerosis (2003),abstract 2P-0401, and Miyata, et al, JP 2004067635), aryl alkyl acidderivatives (see Smith et al, WO2004100881 and US20040224997), furan andthiophene derivatives (see WO2004022551), pyrrolo[1,2b]pyridazinederivatives (see Fox et al, WO2005103907), and substituted sulfonamides(see Budd Haeberlein and Buckett, WO20050442500).

Also known to be inhibitors of DGAT are: 2-bromo-palmitic acid (seeColman et al, Biochimica et Biophysica Acta (1992) 1125, 203-9),2-bromo-octanoic acid (see Mayorek and Bar-Tana, Journal of BiologicalChemistry (1985) 260, 6528-6532), roselipins (see Noriko et al, (Journalof Antibiotics (1999) 52, 815-826), amidepsin (see Tomoda et al, Journalof Antibiotics (1995) 48, 942-7), isochromophilone, prenylflavonoids(see Chung et al, Planta Medica (2004) 70, 258-260), polyacetylenes (seeLee et al, Planta Medica (2004) 70, 197-200), cochlioquinones (see Leeet al, Journal of Antibiotics (2003) 56, 967-969), tanshinones (see Koet al, Archives of Pharmaceutical Research (2002) 25, 446-448),gemfibrozil (see Zhu et al, Atherosclerosis (2002) 164, 221-228), andsubstituted quinolones (see Ko, et al, Planta Medica (2002) 68,1131-1133). Also known to be modulators of DGAT activity are antisenseoligonucleotides (see Monia and Graham, US20040185559).

A need exits in the art, however, for additional DGAT inhibitors thathave efficacy for the treatment of metabolic disorders such as, forexample, obesity, type II diabetes mellitus and metabolic syndrome.Further, a need exists in the art for DGAT inhibitors having IC₅₀ valuesless than about 1 μM.

SUMMARY OF THE INVENTION

In one embodiment of the present invention, provided is a compound ofthe formula (I):

wherein:R₁ is unsubstituted aryl, aryl substituted with a group selected fromthe group consisting of alkyl, —O-alkyl, haloalkoxy, methoxy-ethoxy andhalogen, heteroaryl, alkyl or cycloalkyl;

R₂ is C or N; R₃ is C, N, S or O; R₄ is C, O, S or N; R₅ is C, N or S;

R₆ is H, alkyl, halogen, haloalkyl, thioalkyl or absent;

R₇ is

at least one of R₈ or R₉ is N; andR₁₀ is —NR₁₁R₁₂, O-alkyl, hydroxy-dimethylethylamino,hydroxyl-methylethylamino, cyclohept-2-ylamino, morpholino,thiomorpholino, oxothiomorpholino, dioxothiomorpholino,alkyl-carbamoyl-alkyl-amino, difluoroazetidine, ethoxyazetidine,azetidin-3-yloxy acetic acid tert-butyl ether, azetidine-3-yloxy aceticacid hydrochloride, or a 4- to 6-membered cyclic ring having from 1 to 3hetero ring atoms selected from the group consisting of S, N and O,unsubstituted or substituted with a group selected from the groupconsisting of amino, amide, —N(CH₃)C(O)CH₃, cyclopropanecarbonyl-methyl,—OCH₃, —OCH₂C(O)OC(CH₃)₃, OCH₂C(O)OH, —CH₂OH, —CH₂OCH₃ and —OH;R₁₁ is H, lower alkyl, alkyl ether, alkyl-aryl, trifluoromethyl,methoxymethyl, cyclopropylmethoxy-ethyl, ethoxymethyl, —CH₂CH₂CN, alkylalcohol, acyl, cycloalkyl, or a 4- to 6-membered cyclic ring having from1 to 3 hetero ring atoms selected from the group consisting of S, N andO, unsubstituted or substituted with a group selected from the groupconsisting of —OCH₃, —CH₂OH, —CH₂OCH₃, —OCH₂C(O)OC(CH₃)₃, —OCH₂C(O)OHand —OH;R₁₂ is H or lower alkyl;or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, provided is apharmaceutical composition, comprising a therapeutically effectiveamount of a compound according to formula I or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.

In a further embodiment of the present invention, provided is a methodof treating obesity, type II diabetes or metabolic syndrome, comprisingthe step of administering a therapeutically effective amount of acompound according to formula Ito a patient in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention pertains to DGAT inhibitors that are derivativesof, for example, oxazoles. In a preferred embodiment, the inventionprovides compounds of the formula:

as well as pharmaceutically acceptable salts thereof.

It is to be understood that the terminology employed herein is for thepurpose of describing particular embodiments, and is not intended to belimiting. Further, although any methods, devices and materials similaror equivalent to those described herein can be used in the practice ortesting of the invention, the preferred methods, devices and materialsare now described.

As used herein, the term “alkyl” means, for example, a branched orunbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl oralkynyl)hydrocarbyl radical which may be substituted or unsubstituted.Where cyclic, the alkyl group is preferably C₃ to C₁₂, more preferablyC₄ to C₁₀, more preferably C₄ to C₇. Where acyclic, the alkyl group ispreferably C₁ to C₁₀, more preferably C₁ to C₆, more preferably methyl,ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl ortertiary-butyl) or pentyl (including n-pentyl and isopentyl), morepreferably methyl. It will be appreciated therefore that the term“alkyl” as used herein includes alkyl (branched or unbranched),substituted alkyl (branched or unbranched), alkenyl (branched orunbranched), substituted alkenyl (branched or unbranched), alkynyl(branched or unbranched), substituted alkynyl (branched or unbranched),cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, cycloalkynyl and substituted cycloalkynyl.

As used herein, the term “lower alkyl” means, for example, a branched orunbranched, cyclic or acyclic, saturated or unsaturated hydrocarbylradical wherein said cyclic lower alkyl group is C₅, C₆ or C₇, andwherein said acyclic lower alkyl group is C₁, C₂, C₃ or C₄, and ispreferably selected from methyl, ethyl, propyl (n-propyl or isopropyl)or butyl (n-butyl, isobutyl or tertiary-butyl). It will be appreciatedtherefore that the term “lower alkyl” as used herein includes, forexample, lower alkyl (branched or unbranched) and cycloloweralkyl.

As used herein, the term “aryl” means, for example, a substituted orunsubstituted carbocyclic aromatic group, such as, for example, phenylor naphthyl. The term “heteroaryl”, alone or in combination with othergroups, means a monocyclic or bicyclic radical of 5 to 12 ring atomshaving at least one aromatic ring containing one, two, or three ringheteroatoms selected from N, O, and S, the remaining ring atoms being C,with the understanding that the attachment point of the heteroarylradical will be on an aromatic ring. One or two ring carbon atoms of theheteroaryl group may be replaced with a carbonyl group. The heteroarylgroup described above may be substituted independently with one, two, orthree substituents, preferably one or two substituents such as, forexample, halogen, hydroxy, C₁₋₆ alkyl, halo C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ alkyl sulfonyl, C₁₋₆ alkyl sulfinyl, C₁₋₆ alkylthio, amino, aminoC₁₋₆ alkyl, mono- or di-substituted amino-C₁₋₆ alkyl, nitro, cyano,acyl, carbamoyl, mono- or di-substituted amino, aminocarbonyl, mono- ordi-substituted amino-carbonyl, aminocarbonyl C₁₋₆ alkoxy, mono- ordi-substituted amino-carbonyl-C₁₋₆ alkoxy, hydroxy- C₁₋₆ alkyl,carboxyl, C₁₋₆ alkoxy carbonyl, aryl C₁₋₆ alkoxy, heteroaryl C₁₋₆alkoxy, heterocyclyl C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl C₁₋₆ alkoxy,carbamoyl C₁₋₆ alkoxy and carboxyl C₁₋₆ alkoxy, preferably halogen,hydroxy, C₁₋₆ alkyl, halo C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl sulfonyl,C₁₋₆ alkyl sulfinyl, C₁₋₆ alkylthio, amino, mono-C₁₋₆ alkyl substitutedamino, di-C₁₋₆ alkyl substituted amino, amino C₁₋₆ alkyl, mono-C₁₋₆alkyl substituted amino-C₁₋₆ alkyl, di-C₁₋₆ alkyl substituted amino-C₁₋₆alkyl, nitro, carbamoyl, mono- or di-substituted amino-carbonyl,hydroxy- C₁₋₆ alkyl, carboxyl, C₁₋₆ alkoxy carbonyl and cyano.

The alkyl and aryl groups may be substituted or unsubstituted. Wheresubstituted, there will generally be, for example, 1 to 3 substituentspresent, preferably 1 substituent. Substituents may include, forexample: carbon-containing groups such as alkyl, aryl, arylalkyl (e.g.substituted and unsubstituted phenyl, substituted and unsubstitutedbenzyl); halogen atoms and halogen-containing groups such as haloalkyl(e.g. trifluoromethyl); oxygen-containing groups such as alcohols (e.g.hydroxyl, hydroxyalkyl, aryl(hydroxyl)alkyl), ethers (e.g. alkoxy,aryloxy, alkoxyalkyl, aryloxyalkyl), aldehydes (e.g. carboxaldehyde),ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl,arylalkylcarbonyl, arycarbonylalkyl), acids (e.g. carboxy,carboxyalkyl), acid derivatives such as esters (e.g. alkoxycarbonyl,alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl), amides(e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl, aminocarbonylalkyl,mono- or di-alkylaminocarbonylalkyl, arylaminocarbonyl), carbamates(e.g. alkoxycarbonylamino, arloxycarbonylamino, aminocarbonyloxy, mono-or di-alkylaminocarbonyloxy, arylminocarbonloxy) and ureas (e.g. mono-or di-alkylaminocarbonylamino or arylaminocarbonylamino);nitrogen-containing groups such as amines (e.g. amino, mono- ordi-alkylamino, aminoalkyl, mono- or di-alkylaminoalkyl), azides,nitriles (e.g. cyano, cyanoalkyl), nitro; sulfur-containing groups suchas thiols, thioethers, sulfoxides and sulfones (e.g. alkylthio,alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, arylthio, arysulfinyl, arysulfonyl, arythioalkyl,arylsulfinylalkyl, arylsulfonylalkyl); and heterocyclic groupscontaining one or more, preferably one, heteroatom, (e.g. thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl,pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl,piperidyl, hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl,benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl, isoindolyl,indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl,isocoumarinyl, quinolinyl, isoquinolinyl, naphthridinyl, cinnolinyl,quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl,chromanyl, isochromanyl, phthalazinyl and carbolinyl).

The lower alkyl groups may be substituted or unsubstituted, preferablyunsubstituted. Where substituted, there will generally be, for example,1 to 3 substitutents present, preferably 1 substituent.

As used herein, the term “alkoxy” means, for example, alkyl-o- and“alkoyl” means, for example, alkyl-CO—. Alkoxy substituent groups oralkoxy-containing substituent groups may be substituted by, for example,one or more alkyl groups.

As used herein, the term “halogen” means, for example, a fluorine,chlorine, bromine or iodine radical, preferably a fluorine, chlorine orbromine radical, and more preferably a fluorine or chlorine radical.

As used herein, the term “pharmaceutically acceptable salt” means anypharmaceutically acceptable salt of the compound of formula (I). Saltsmay be prepared from pharmaceutically acceptable non-toxic acids andbases including inorganic and organic acids and bases. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic,glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic,maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic,p-toluenesulfonic and the like. Particularly preferred are fumaric,hydrochloric, hydrobromic, phosphoric, succinic, sulfuric andmethanesulfonic acids. Acceptable base salts include alkali metal (e.g.sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) andaluminium salts.

Compounds of the present invention can be prepared beginning withcommercially available starting materials and utilizing generalsynthetic techniques and procedures known to those skilled in the art.Outlined below are reaction schemes suitable for preparing suchcompounds. Further exemplification is found in the specific Examplesdetailed below.

As shown in Scheme 1, using a method similar to Gilman and Burtner (seeH. Gilman and R. R. Burtner J. Amer. Chem. Soc. 71 1213 (1949)),2-substituted-3-furoic acid i, where R′ is halogen, lower alkyl,haloalkyl, alkoxy, thioalkoxy, haloalkoxy, can be brominated at C-5 withbromine in acetic acid to give 5-bromo-furoic acid ii. Furoic acid iican be reacted to form amide iii with various amines, where R₁′ is aryl,substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl orcycloheteroalkyl. Various standard amide bond forming conditions, aspracticed by those skilled in the art, may be used. Typically ii and anamine NH₂R₁′, in an appropriate solvent, may be treated with a base,such as triethyl amine, and an amide bond forming reagent such as BOP,PyBroP or EDCI and HOBT (see D. Nguyen J. Chem. Soc. Perkin Trans. I1025 (1985), J. Coste et al J. Org. Chem. 59 2437 (1994) and M Boyemanet al Int. J. Peptide Protein Res. 37 252 (1991)) to yield amide iii.Using standard palladium catalyzed “cross coupling” procedures (see A.Suzuki, in Metal-Catalyzed Cross-Coupling Reaction, Diederich F, StangP. J, eds, Wiley, 1998 pp 49-97 and F. Bellina et al Synthesis 2419(2004)), 5-bromo-furoic acid amide iii can be heated with a commerciallyavailable substituted phenylboronic acid or boronate ester in thepresence of a base, typically an aqueous solution of sodium carbonate,in an appropriate solvent, typically, DME, DMF or toluene, with acatalytic amount of palladium, typically Pd[PPh₃]₄, to yield iv, whereR₂′ is aryl, substituted aryl, heteroaryl, substituted heteroaryl.

As shown in Scheme 2, pyrazole vi could be prepared using a methodsimilar to that used by Varano, F. et al (J. Med. Chem. 2002, 45, 1035)in which the keto ester v can be treated with hydrazine hydrate withheating in a solvent such as ethanol to give pyrazole vi, where R₃′ isaryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl,cycloalkyl, and R₄′ is lower alkyl, preferably methyl or ethyl. Pyrazolevi can be alkylated under basic conditions, preferably sodium hydride asbase, as described by Zhang, J. et al (Bioorg. Med. Chem. Lett. 2000,10, 2575) to give predominantly isomer vii.

Substituted pyrazole ester vii can be hydrolyzed by heating with astrong base, typically sodium hydroxide in an aqueous/organic mixedsolvent, preferred is methanol, to give the pyrazole acid viii.

Pyrazole acid viii can be reacted to form amides with various amines,where R₁′ is aryl, substituted aryl, heteroaryl, substituted heteroaryl,cycloalkyl or cycloheteroalkyl. Various standard amide bond formingconditions, as practiced by those skilled in the art, may be used.Typically viii and an amine NH₂R₁′, in an appropriate solvent, may betreated with a base, such as triethyl amine, and an amide bond formingreagent such as BOP, PyBroP or EDCI and HOBT to yield amide ix.

As shown in Scheme 3, using a method similar to Plouvier et al (see B.Plouvier et al Heterocycles 32 693 (1991)), the 2-hydroxy-alkyl acidester x, R′ is lower alkyl, haloalkyl, alkoxy, thioalkoxy, haloalkoxyand R₄′ is lower alkyl, preferably methyl or ethyl, can be reacted withN-bromosuccimide in CCl₄ under reflux to give xi. The keto bromide xiupon heating, preferably in a microwave reactor, with urea in anappropriate solvent, preferably ethanol, cyclizes to yield substituted2-amino oxazole xii. Heating of xii with cupric (II) bromide andt-butylnitrite in dry acetonitrile under argon yields 2-bromo-oxazolexiii.

The substituted 2-bromo-oxazole ester xiii can be can be hydrolyzed byheating with a strong base, typically sodium hydroxide in anaqueous/organic mixed solvent, preferred is methanol, to give thebromo-oxazole acid xiv.

Oxazole acid xiv can be reacted to form amides with various amines,where R₁′ is aryl, substituted aryl, heteroaryl, substituted heteroaryl,cycloalkyl or cycloheteroalkyl. Various standard amide bond formingconditions, as practiced by those skilled in the art, may be used.Typically xiv and an amine NH₂R₁′, in an appropriate solvent, may betreated with a base, such as triethyl amine, and an amide bond formingreagent such as BOP, PyBroP or EDCI and HOBT to yield amide xv.

Using standard palladium catalyzed “cross coupling” procedures,2-oxazole acid amide xv can be heated with a commercially availablesubstituted phenylboronic acid or boronate ester in the presence of abase, typically an aqueous solution of sodium carbonate, in anappropriate solvent, typically, DME, DMF or toluene, with a catalyticamount of palladium, typically Pd[PPh₃]₄, to yield xiv, where R₂′ isaryl, substituted aryl, heteroaryl, substituted heteroaryl.

As shown in Scheme 4, ester xvii, where R₄′ is lower alkyl, preferablymethyl or ethyl, and R₅′ is alkyl, branched alkyl, cycloalkyl orcycloheteroalkyl, can be reduced with various reducing agents,preferably DIBAL, to yield aldehyde xviii. Using a method similar toKretchmer and Laiter (see R. A. Kretchmer and R. A. Laitar J. Org. Chem.43 4596 (1978)), aldehyde xviii can be reacted with ethyl acetoacetateand a weak base, such as piperidine, to give xix. Upon heating with NBSin CCl₄ and distillation, xix yields substituted furan xx.

The substituted ester xx can be can be hydrolyzed by heating with astrong base, typically sodium hydroxide in an aqueous/organic mixedsolvent, preferred is methanol, to give the 3-furoic acid xxi.

Furoic acid xxi can be reacted to form amides with various amines, whereR₁′ is aryl, substituted aryl, heteroaryl, substituted heteroaryl,cycloalkyl or cycloheteroalkyl. Various standard amide bond formingconditions, as practiced by those skilled in the art, may be used.Typically xxi and an amine NH₂R₁′, in an appropriate solvent, may betreated with a base, such as triethyl amine, and an amide bond formingreagent such as BOP, PyBroP or EDCI and HOBT to yield amide xxii.

As shown in Scheme 5, commercially available nitro aryl halide xxiii,where A and B can be CH or N and X is F, Cl or Br, can be treated with anucleophile, typically an amine or an alcohol, and a neutralizing base,typically Et₃N, in an appropriate solvent, typically dichloromethane orN,N-dimethylformamide with or without heating to yield the correspondingsubstituted nitro aryl xxiv, where Nu can be a substituted orunsubstituted cyclic amine, such as morpholin, thiomorpholin,pyrrolidine, piperidine, mono or disubstituted amine, amino acid or analkoxy group. The nitro group in compound xxiv can be reduced in anappropriate solvent, typically ethyl acetate or methanol under pressureof hydrogen, typically 50 psi, in presence of a catalyst; typically 10%palladium on carbon, to give substituted aniline xxv.

As shown in Scheme 6, the mono substituted nitro aryl aniline xxvi,prepared according to the procedure described in Scheme 5, where R₆′ islower alkyl, was acylated with an acylating agent, typically an acidchloride or an anhydride, in an appropriate solvent, typically pyridine,in presence of a catalytic amount of 4-dimethylaminopyridine withheating to give N-alkyl-4 nitro-aryl-amide xxvii, where R₇′ is loweralkyl. The nitro group in amide xxvii is reduced in an appropriatesolvent, typically ethyl acetate or methanol under pressure of hydrogen,typically 50 psi, in presence of a catalyst; typically 10% palladium oncarbon, to give aniline xxviii.

As shown in Scheme 7, compound xxix, prepared according to the proceduredescribed in Scheme 5, can be treated with a base, typically sodiumhydride and an alkylating agent, typically alkyl iodide in anappropriate solvent, typically N,N-dimethylformamide, to give N and/or Oalkylated nitro compound xxx, which again can be reduced under pressureof hydrogen, typically 50 psi, in presence of a catalyst, typically 10%palladium on carbon, to give aniline xxxi.

As shown in Scheme 8, oxazole compound xxxv can be prepared according tothe procedure described in Org. Lett, 2003, 5 (24), 4567. Compoundxxxii, commercially available or prepared according to the proceduredescribed in Bioorg. Med. Chem. Lett. 2001, 11 (15), 1975, where R₄′ islower alkyl, benzyl or other protecting groups, can be treated with astrong base, typically lithium bis(trimethylsilyl)amide, and ananhydride or an acid chloride, where R′ can be a lower alkyl, cycloalkylor cycloheteroalkyl, in an appropriate solvent, typicallytetrahydrofuran, to give the keto ester xxxiii. The diphenyl iminexxxiii can be hydrolyzed with 2 N HCl aqueous solution in THF to give anamine HCl salt which can be acylated with an acid chloride or ananhydride in presence of pyridine in an appropriate solvent, typicallydichloromethane to give compound xxxiv, where R₃′ is aryl, substitutedaryl, heteroaryl, substituted heteroaryl, alkyl, or cycloalkyl. Theoxazole ring can be generated by mixing compound xxxiv,triphenylphosphine and iodine in tetrahydrofuran with cooling. Theoxazole ester xxxv can be hydrolyzed by treating with a base, typicallylithium hydroxide in an aqueous/organic mixed solvent to give theoxazole-4-carboxylic acid xxxvi.

The acid xxxvi can be reacted to form amides with various amines, whereR₁′ is aryl, substituted aryl, heteroaryl, substituted heteroaryl,cycloalkyl or cycloheteroalkyl. Various standard amide bond formingconditions, as practiced by those skilled in the art, may be used.Typically, the acid xxxvi and an amine NH₂R₁′, in an appropriatesolvent, may be treated with a base, such as triethyl amine, and anamide bond forming reagent such as BOP, PyBrop, or EDCI and HOBT toyield amide xxxvii.

Scheme 9 describes general synthesis of oxazole amide xxxvii bearing ahalogen group at C-5. Using standard palladium catalyzed “crosscoupling” procedures, 2-chloro-oxazole-4-carboxylic acid alkyl ester,where R₄′ is a lower alkyl, preferably methyl or ethyl, preparedaccording to the procedure described in J. Med. Chem. 1971, 14 (11),1075; Org. Lett. 2002, 4 (17), 2905 and J. Org. Chem. 1977, 42, 2429,can be heated with a commercially available substituted or unsubstitutedarylboronic acid or boronate ester in the presence of a base, typicallyan aqueous solution of sodium carbonate, in an appropriate solvent,typically, DME, DMF or Toluene, with a catalytic amount of palladium,typically Pd(PPh₃)₄, to yield xxxix, where R₂′ is aryl, substitutedaryl, heteroaryl, or substituted heteroaryl. The oxazole ester xxxix canbe chlorinated or brominated at C5 position with 1-chloro-pyrrolidine2,5-dione or 1-bromo-pyrrolidine 2,5-dione by heating up to 90° C. inchloroform in presence of a catalytic amount of concentrated sulfuricacid to yield compound xxxx. The ester xxxx can be hydrolyzed bytreating with a base, typically lithium hydroxide in an aqueous/organicmixed solvent to give the oxazole-4-carboxylic acid xxxxi.

Acid xxxxi can be reacted to form amides with various amines, where R₁′is aryl, substituted aryl, heteroaryl, substituted heteroaryl,cycloalkyl or cycloheteroalkyl. Various standard amide bond formingconditions, as practiced by those skilled in the art, may be used.Typically, acid xxxxi and an amine NH₂R₁′, in an appropriate solvent,may be treated with a base, such as triethyl amine, and an amide bondforming reagent such as BOP, PyBrop, or EDCI and HOBT to yield amidexxxvii.

Scheme 10 describes an alternative synthesis of oxazole amide xxxxviibearing trifluoromethyl at C-5 position. The glycine ester, where R₄′ islower alkyl, preferably methyl or ethyl, was acylated with an acylatingagent, typically an acid chloride or an anhydride, where R₃′ is aryl,substituted aryl, heteroaryl, substituted heteroaryl, alkyl, orcycloalkyl. After acylation, the ester can be hydrolyzed by treatingwith a base, typically lithium hydroxide, in an aqueous/organic solvent,preferred is methanol, to give acid xxxxiii. To the solution of acidxxxxiii in acetone was added excess of trifluoroacetic anhydride withcooling to give a stable ketone hydrate, which was then refluxed inmethanol for 30 min to give ketone hydrate methyl ester xxxxiv. Compoundxxxxiv upon heating with phosphorus oxychloride cyclizes to yieldsubstituted oxazole ester xxxxv, which was again hydrolyzed with a base,typically lithium hydroxide, in an aqueous/organic mixed solvent,preferred is methanol, to give oxazole acid xxxxvi.

Oxazole acid xxxxvi can be reacted to form amides with various amines,where R₁′ is aryl, substituted aryl, heteroaryl, substituted heteroaryl,cycloalkyl or cycloheteroalkyl. Various standard amide bond formingconditions, as practiced by those skilled in the art, may be used.Typically, acid xxxxvi and an amine NH₂R₁′, in an appropriate solvent,may be treated with a base, such as triethyl amine, and an amide bondforming reagent such as BOP, PyBrop, or EDCI and HOBT to yield amidexxxxvii.

As shown in Scheme 11, commercially available amino acid xxxxviii, whereR′ can be lower alkyl, cycloalkyl, or cycloheteroalkyl, can be acylatedwith an acylating agent, typically an acid chloride or an anhydride,according to the procedure described in Int. J. Peptide Protein Res.1989, 33, 353. Using a procedure described in J. Chem. Soc. Chem.Commun. 1995, 2335, acid xxxxix can be treated with excess oxalylchloride with heating in a solvent such as tetrahydrofuran to givecyclized oxazole l, which was directly converted into active ester li byheating with 1-hydroxy-pyrrolidine-2,5-dione and a base, such astriethylamine, in acetonitrile.

Oxazole acid li can be reacted with various amines to form amides lii byheating in an appropriate solvent, typically acetonitrile, where R₁′ isaryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkylor cycloheteroalkyl.

As shown in Scheme 12, aromatic heterocyclic amines lvi can be preparedthrough a Curtius rearrangement reaction. Commercially available arylhalide carboxylic acid methyl ester liii (where X can be nitrogen) isreacted with a nucleophile, Nu, typically an amine or an alcohol, in thepresence of a base such as triethyl amine. The nucleophilic amine can benon-cyclic, cyclic with or without substitution, or heterocyclic. Theresulting ester liv can be saponified to give the correspondingcarboxylic acid, which is transformed to an isocyanate intermediatethrough Curtius rearrangement reaction in the presence ofdiphenylphosphoryl azide and appropriate base such as triethyl amine.The isocyanate intermediate can be reacted with alcohols (where R₈′ canbe tert-butyl or benzyl) to generate the corresponding carbamate lv.Finally the tert-butyl or benzyl carbamate can be deprotected underacidic conditions such as trifluoroacetic acid or under palladiumcatalyzed hydrogenation to generate the desired aromatic heterocyclicamines lvi.

As shown in Scheme 13, amides lix, where R₃′ is aryl, substituted aryl,heteroaryl, substituted heteroaryl, alkyl, or cycloalkyl, where R₁′ canbe aryl, substituted aryl, heteroaryl, substituted heteroaryl,cycloalkyl or cycloheteroalkyl, R′ can be lower alkyl, cycloalkyl,cycloheteroalkyl or null, and R₃′ can be aryl, substituted aryl,heteroaryl, substituted heteroaryl, alkyl, or cycloalkyl, can beprepared from commercially available substituted aromatic acids lviii,where R₈′, R₉′, R₁₀′, and R₁₁′ can independently be N, C, or S, alsoprepared from commercially available esters lvii, where R₄′ is loweralkyl, preferably methyl or ethyl, following hydrolysis, and variousamines. Various standard amide bond forming conditions, as practiced bythose skilled in the art, may be used. Typically, acid lviii and anamine NH₂R₁′, in an appropriate solvent, may be treated with a base,such as triethyl amine, and an amide bond forming reagent such as BOP,PyBrop, or EDCI and HOBT to yield amide lix.

In the practice of the method of the present invention, an effectiveamount of any one of the compounds of this invention or a combination ofany of the compounds of this invention or a pharmaceutically acceptablesalt thereof, is administered via any of the usual and acceptablemethods known in the art, either singly or in combination. The compoundsor compositions can thus be administered orally (e.g., buccal cavity),sublingually, parenterally (e.g., intramuscularly, intravenously, orsubcutaneously), rectally (e.g., by suppositories or washings),transdermally (e.g., skin electroporation) or by inhalation (e.g., byaerosol), and in the form or solid, liquid or gaseous dosages, includingtablets and suspensions. The administration can be conducted in a singleunit dosage form with continuous therapy or in a single dose therapy adlibitum. The therapeutic composition can also be in the form of an oilemulsion or dispersion in conjunction with a lipophilic salt such aspamoic acid, or in the form of a biodegradable sustained-releasecomposition for subcutaneous or intramuscular administration.

Useful pharmaceutical carriers for the preparation of the compositionshereof, can be solids, liquids or gases; thus, the compositions can takethe form of tablets, pills, capsules, suppositories, powders,enterically coated or other protected formulations (e.g. binding onion-exchange resins or packaging in lipid-protein vesicles), sustainedrelease formulations, solutions, suspensions, elixirs, aerosols, and thelike. The carrier can be selected from the various oils including thoseof petroleum, animal, vegetable or synthetic origin, e.g., peanut oil,soybean oil, mineral oil, sesame oil, and the like. Water, saline,aqueous dextrose, and glycols are preferred liquid carriers,particularly (when isotonic with the blood) for injectable solutions.For example, formulations for intravenous administration comprisesterile aqueous solutions of the active ingredient(s) which are preparedby dissolving solid active ingredient(s) in water to produce an aqueoussolution, and rendering the solution sterile. Suitable pharmaceuticalexcipients include starch, cellulose, talc, glucose, lactose, talc,gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodiumstearate, glycerol monostearate, sodium chloride, dried skim milk,glycerol, propylene glycol, water, ethanol, and the like. Thecompositions may be subjected to conventional pharmaceutical additivessuch as preservatives, stabilizing agents, wetting or emulsifyingagents, salts for adjusting osmotic pressure, buffers and the like.Suitable pharmaceutical carriers and their formulation are described inRemington's Pharmaceutical Sciences by E. W. Martin. Such compositionswill, in any event, contain an effective amount of the active compoundtogether with a suitable carrier so as to prepare the proper dosage formfor proper administration to the recipient.

The dose of a compound of the present invention depends on a number offactors, such as, for example, the manner of administration, the age andthe body weight of the subject, and the condition of the subject to betreated, and ultimately will be decided by the attending physician orveterinarian. Such an amount of the active compound as determined by theattending physician or veterinarian is referred to herein, and in theclaims, as a “therapeutically effective amount”. For example, the doseof a compound of the present invention is typically in the range ofabout 1 to about 1000 mg per day. Preferably, the therapeuticallyeffective amount is in an amount of from about 1 mg to about 500 mg perday

The invention will now be further described in the Examples below, whichare intended as an illustration only and do not limit the scope of theinvention.

EXAMPLES

The Examples which follow are for purposes of illustration and are notintended to limit the invention in any way.

General Methods: Melting points were taken on a Thomas-Hoover apparatusand are uncorrected. Optical rotations were determined with aPerkin-Elmer model 241 polarimeter. 1H-NMR spectra were recorded withVarian XL-200, Mercury-300 or Unityplus 400 MHz spectrometers.Tetramethylsilane (TMS) may ne used as internal standard. Electronimpact (E1, 70 ev) and fast atom bombardment (FAB) mass spectra weretaken on VG Autospec or VG 70E-HF mass spectrometers. Silica gel usedfor column chromatography was Mallinkrodt SiliCar 230-400 mesh silicagel for flash chromatography; columns were run under a 0-5 psi head ofnitrogen to assist flow. Thin layer chromatograms were run on glass thinlayer plates coated with silica gel as supplied by E. Merck (E. Merck #1.05719) and were visualized by viewing under 254 nm UV light in a viewbox, by exposure to I₂ vapor, or by spraying with either phosphomolybdicacid (PMA) in aqueous ethanol, or after exposure to Cl₂, with a4,4′-tetramethyldiaminodiphenylmethane reagent prepared according to E.Von Arx, M. Faupel and M Brugger, J. Chromatography, 1976, 220, 224-228.

Reversed phase high pressure liquid chromatography (RP-HPLC) was carriedout using a Rainin HPLC employing a 41.4×300 mm, 8 μm. Dynamax™ C-18column at a flow of 49 mL/min employing a gradient of acetonitrile:water(each containing 0.75% TFA) typically from 5 to 95% acetonitrile over35-40 min. HPLC conditions are typically described in the format(5-95-35-214); this refers to a linear gradient of from 5% to 95%acetonitrile in water over 35 min while monitoring the effluent with aUV detector at a wavelength of 214 nm.

Preparative supercritical fluid chromatography (SFC) was performed onBerger MultiGram II Supercritical Fluid Chromatography system (ModelSD-1) from Mettler-Toledo AutoChem Berger Instruments, Newark, Del.,USA. The system consisted of an automatic liquid injection system with aDAICEL AD chiral column, 5 mL loop used to make injections and a thermalcontrol module (TCM) used to control column temperature. Chromatographicconditions: SFC separations were performed at a temperature of 30° C., aflow rate of 70 mL/min, and CO₂ pressure of 100 bar. Knauer variablewavelength UV detector (supplied by Mettler-Toledo) with high pressureflow cell was used for SFC detection. Detection in SFC was performed bymeasurement of UV absorbance at 220 nm.

Methylene chloride (dichloromethane), 2-propanol, DMF, THF, toluene,hexane, ether, and methanol, were Fisher or Baker reagent grade and wereused without additional purification except as noted, acetonitrile wasFisher or Baker HPLC grade and was used as is.

Definitions as used herein:

-   DGAT is diacylglycerol:acyl CoA O-acyltransferase,-   THF is tetrahydrofuran,-   DMF is N,N-dimethylformamide,-   DMA is N,N-dimethylacetamide,-   DMSO is dimethylsulfoxide,-   DCM is dichloromethane,-   DME is dimethoxyethane,-   MeOH is methanol,-   EtOH is ethanol,-   NaOH is sodium hydroxide,-   NBS is N-bromosuccinimide,-   TFA is 1,1,1-trifluoroacetic acid,-   HOBT is 1-hydroxybenzotriazole,-   PyBroP is bromotripyrrolidinophosphonium hexafluorophosphate,-   EDCI is 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide    hydrochloride,-   DIPEA is diisopropylethylamine,-   brine is saturated aqueous sodium chloride solution,-   DAG is 1,2-dioleoyl-sn-glycerol,-   TLC is thin layer chromatography,-   RP HPLC is reversed phase high performance liquid chromatography,-   APCI-MS is atmospheric pressure chemical ionization mass    spectrometry,-   ES-MS is electrospray mass spectrometry,-   LCMS is liquid chromatography mass spectrometry,-   RT is room or ambient temperature.

Silica gel chromatography on Biotage columns refers to use of a flashchromatography system supplied by the Biotage Division of the DyaxCorporation employing prepacked 40 g (40 s columns), 90 g (40 m columns)or 800 g (75 m columns). Elution is carried out with hexane-ethylacetate mixtures under 10-15 psi nitrogen pressure.

Part I: Intermediates Preparation of 6-morpholin-4-yl-pyridin-3-ylamine

A mixture of 2-chloro-5-nitro-pyridine (5 g, 31 mmol), morpholine (13mL, 155 mmol), and triethylamine (10 mL) in dichloromethane (30 mL) wasstirred at room temperature for 3 hr. After the reaction, the reactionmixture was mixed with water, and two layers were separated. The aqueouslayer was extracted with CH₂Cl₂ two times. Organic layers werecollected, combined, washed with brine, dried over sodium sulfate,filtered, and concentrated to give 4-(5-nitro-pyridin-2-yl)-morpholine(6.48 gm, 100%) as a yellow solid. LCMS calcd for C9H11N3O3 (m/e) 209,obsd 210 (M+H).

The solution of 4-(5-nitro-pyridin-2-yl)-morpholine (1.5 g, 7.18 mmol)in ethyl acetate (20 mL) in the presence of 10% palladium on carbon(0.75 g) was shaken under the hydrogen with a pressure of 50 psi at roomtemperature for 3 hr. After the reaction, the reaction mixture wasfiltered through a plug of celite and the filtration pad was washed withethyl acetate. The organic layer was collected, concentrated, and driedto give 6-morpholin-4-yl-pyridin-3-ylamine (1.11 g, crude) as a lightred solid, which was directly used in the next step reaction withoutfurther purification. LCMS calcd for C9H14N3O (m/e) 179, obsd 180 (M+H).

Preparation of 2-morpholin-4-yl-pyrimidin-5-ylamine

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,2-morpholin-4-yl-pyrimidin-5-ylamine was prepared from2-chloro-5-nitro-pyrimidine and morpholine. LCMS calcd for C8H12N4O(m/e) 180, obsd 181 (M+H).

Preparation of 6-thiomorpholin-4-yl-pyridin-3-ylamine

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,6-thiomorpholin-4-yl-pyridin-3-ylamine was prepared from2-chloro-5-nitro-pyridine and thiomorpholine. LCMS calcd for C9H13N3S(m/e) 195, obsd 196 (M+H).

Preparation ofN-[1-(5-amino-pyridin-2-yl)-pyrrolidin-3-yl]-N-methyl-acetamide

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,N-[1-(5-amino-pyridin-2-yl)-pyrrolidin-3-yl]-N-methyl-acetamide wasprepared from 2-chloro-5-nitro-pyridine andN-methyl-N-pyrrolidin-3-yl-acetamide. LCMS calcd for C12H18N4O (m/e)234, obsd 235 (M+H).

Preparation of 2-(5-amino-pyridin-2-ylamino)-ethanol

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,2-(5-amino-pyridin-2-ylamino)-ethanol was prepared from2-chloro-5-nitro-pyridine and 2-amino-ethanol. LCMS calcd for C7H11N3O(m/e) 153, obsd 154 (M+H).

Preparation of 2-(2-methoxy-ethyl)-pyridine-2,5-diamine

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,2-(2-methoxy-ethyl)-pyridine-2,5-diamine was prepared from2-chloro-5-nitro-pyridine and 2-methoxy-ethylamine. LCMS calcd forC8H13N3O (m/e) 167, obsd 168 (M+H).

Preparation of N²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,N²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine was prepared from2-chloro-5-nitro-pyridine and (2-methoxy-ethyl)-methyl-amine. LCMS calcdfor C9H15N3O (m/e) 181, obsd 182 (M+H).

Preparation of 6-(2-methoxy-ethoxy)-pyridin-3-ylamine

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,6-(2-methoxy-ethoxy)-pyridin-3-ylamine was prepared from2-chloro-5-nitro-pyridine and 2-methoxy-ethanol. LCMS calcd forC8H12N2O2 (m/e) 168, obsd 169 (M+H).

Preparation of 2-[(5-amino-pyridin-2-yl)-methyl-amino]-ethanol

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,2-[(5-amino-pyridin-2-yl)-methyl-amino]ethanol was prepared from2-chloro-5-nitro-pyridine and 2-methylamino-ethanol. LCMS calcd forC8H13N3O (m/e) 167, obsd 168 (M+H).

Preparation of N²-(3-methoxy-propyl)-N²-methyl-pyridine-2,5-diamine

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,N²-(3-methoxy-propyl)-N²-methyl-pyridine-2,5-diamine was prepared from2-chloro-5-nitro-pyridine and (3-methoxy-propyl)-methyl-amine. LCMScalcd for C10H17N3O (m/e) 195, obsd 196 (M+H).

Preparation of N²-(3-methoxy-propyl)-pyridine-2,5-diamine

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,N²-(3-methoxy-propyl)-pyridine-2,5-diamine was prepared from2-chloro-5-nitro-pyridine and 3-methoxy-propylamine. LCMS calcd forC9H15N3O (m/e) 181, obsd 182 (M+H).

Preparation of N²-ethyl-N²-(2-methoxy-ethyl)-pyridine-2,5-diamine

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,N²-ethyl-N²-(2-methoxy-ethyl)-pyridine-2,5-diamine was prepared from2-chloro-5-nitro-pyridine and ethyl-(2-methoxy-ethyl)-amine. LCMS calcdfor C10H17N3O (m/e) 195, obsd 196 (M+H).

Preparation of N²-butyl-N²-methyl-pyridine-2,5-diamine

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,N²-butyl-N²-methyl-pyridine-2,5-diamine was prepared from2-chloro-5-nitro-pyridine and butyl-methyl-amine. LCMS calcd forC10H17N3 (m/e) 179, obsd 180 (M+H).

Preparation of N²-methyl-N²-propyl-pyridine-2,5-diamine

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,N²-methyl-N²-propyl-pyridine-2,5-diamine was prepared from2-chloro-5-nitro-pyridine and methyl-propyl-amine. LCMS calcd forC9H15N3 (m/e) 165, obsd 166 (M+H).

Preparation of N²-ethyl-N²-methyl-pyridine-2,5-diamine

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,N²-ethyl-N²-methyl-pyridine-2,5-diamine was prepared from2-chloro-5-nitro-pyridine and ethyl-methyl-amine. LCMS calcd for C8H13N3(m/e) 151, obsd 152 (M+H).

Preparation of N²-ethyl-pyridine-2,5-diamine

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above, N²-ethyl-pyridine-2,5-diaminewas prepared from 2-chloro-5-nitro-pyridine and ethyl-amine. LCMS calcdfor C7H11N3 (m/e) 137, obsd 138 (M+H).

Preparation of N²,N²-diethyl-pyridine-2,5-diamine

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,N²,N²-diethyl-pyridine-2,5-diamine was prepared from2-chloro-5-nitro-pyridine and diethyl-amine. LCMS calcd for C9H15N3(m/e) 165, obsd 166 (M+H).

Preparation of N²-isopropyl-N²-methyl-pyridine-2,5-diamine

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,N²-Isopropyl-N²-methyl-pyridine-2,5-diamine was prepared from2-chloro-5-nitro-pyridine and isopropyl-methyl-amine. LCMS calcd forC9H15N3 (m/e) 165, obsd 166 (M+H).

Preparation of N²,N²-dimethyl-pyridine-2,5-diamine

A mixture of 2-chloro-5-nitro-pyridine (500 mg, 3.15 mmol), in DMF (2mL) was added dropwise to a suspension of NaH (151 mg, 6.31 mmol) in DMF(2 mL). The reaction mixture was stirred at room temperature for onehour then heated to 55° C. overnight. The reaction mixture was thenpoured into ice water, extracted with EtOAc, washed with brine, driedover sodium sulfate, filtered and concentrated to givedimethyl-(5-nitro-pyridin-2-yl)-amine as a yellow solid. LCMS calcd forC7H11N3 (m/e) 137, obsd 138 (M+H).

A solution of dimethyl-(5-nitro-pyridin-2-yl)-amine (100 mg, 0.47 mmol)and 10% palladium on carbon (0.05 g) in methanol (5 mL) was shaken under50 psi hydrogen atmospheres at room temperature for 3 h. The reactionmixture was then filtered through a plug of celite and the filtrationpad was washed with ethyl acetate. The organic layers were collected,concentrated, and dried to give N²,N²-dimethyl-pyridine-2,5-diamine (90mg crude) as a light red oil, which was directly used in the next stepwithout further purification.

Preparation of N²-cyclopentyl-pyridine-2,5-diamine

To a 20 mL vial containing cyclopentylamine (300 mg, 3.53 mmol) wasadded DMF (5 mL), 2-chloro-5-nitro-pyridine (559 mg, 3.53 mmol), and theTEA (0.98 mL). The vessel was purged with argon, sealed, and heat bymicrowave at 200° C. for 5 min (Personal Chemistry, Emrys Optimizer).The reaction mixture was concentrated, diluted with water (100 mL) andextracted with ethyl acetate. The organic layer was washed withsaturated sodium bicarbonate (100 mL) and brine (100 mL), dried oversodium sulfate, and evaporated to givecyclopentyl-(5-nitro-pyridin-2-yl)-amine. LCMS calcd. C₁₀H₁₃N₃O₂ (m/e)207, observed 208 (M+H). This intermediate nitropyridyl compound wastransferred to a PARR vessel with MeOH (5 mL), Pd/C (10%) was added andthe vessel was pressurized with H₂ at 55 psi and shaken for 2.5 hr. Themixture was then filtered through a bed of celite and concentrated todryness twice from CH₂Cl₂. The purple black material was usedimmediately for amide coupling (LCMS calcd. for C₁₀H₁₅N₃ (m/e) 177,observed 178 (M+H).

Preparation of N²-cyclohexyl-pyridine-2,5-diamine

With a method similar to that used for the preparation ofcyclopentyl-pyridine-2,5-diamine above,N²-cyclohexyl-pyridine-2,5-diamine was prepared from2-chloro-5-nitro-pyridine and cyclohexyl amine. LCMS for C₁₁H₁₇N₃calculated (m/e) 191, observed 192 (M+H).

Preparation of N²-cyclopropyl-pyridine-2,5-diamine

With a method similar to that used for the preparation ofcyclopentyl-pyridine-2,5-diamine, N²-cyclopropyl-pyridine-2,5-diaminewas prepared from 2-chloro-5-nitro-pyridine and cyclopropyl amine. (LCMScalculated for C₈H₁₁N₃ (m/e) 149, observed 150 (M+H).

Preparation of N²-cyclopropyl-N²-methyl-pyridine-2,5-diamine

The intermediate, cyclopropyl-(5-nitro-pyridin-2-yl)-amine, from theabove procedure, was methylated with methyl iodide. To a 2 mL microwavevial was added cyclopropyl-(5-nitro-pyridin-2-yl)-amine (146 mg, 0.812mmol), DMF (2 mL), potassium carbonate (224 mg, 1.62 mmol), and the MeI(56 μl, 0.893 mmol). The mixture was heated by microwave for two 10 minincrements at 200° C. using a Personal Chemistry, Emrys

Optimizer. Then followed addition of another portion of MeI (56 μL,0.893 mmol) microwave at 200° C. for 10 min and then conventionalheating at 70° C. for 15 hr. At the end of this period a third additionof MeI (56 μL, 0.893 mmol) took place and the mixture was heated bymicrowave once more for 10 min at 200° C. The reaction mixture was thenconcentrated to dryness, suspended in ethyl acetate (100 mL) and washedwith water (100 mL) two times and one time with brine. The aqueouslayers were combined and extracted once with ethyl acetate (50 mL). Thecombined organic layer was washed once with brine (100 mL),concentrated, supported onto silica gel, and purified by flashchromatography using the Analogix system with a 12 g Silicycle silicagel column with increasing concentrations of ethyl acetate in hexanes(20 mL/min, equilibrate with 0%, 0 to 5 min: 0%; 5 to 25 min: 0 to 30%;25-45 min: 30%). The appropriate fractions were collected and dried toafford 90 mg of cyclopropyl-methyl-(5-nitro-pyridin-2-yl)-amine, ayellow solid (yield 57%). LCMS calcd. for C₉H₁₁N₃O₂ (m/e) 193, observed194 (M+H). This intermediate nitropyridyl compound was then reduced, asdescribed in the preparation of cyclopentyl-pyridine-2,5-diamine above,to afford N²-cyclopropyl-N²-methylpyridine-2,5-diamine. LCMS calcd. forC₉H₁₃N₃ (m/e) 163, observed 164 (M+H).

Preparation of N²-cyclobutyl-N²-methyl-pyridine-2,5-diamine

With a similar method used for the preparation ofcyclopentyl-(5-nitro-pyridin-2-yl)-amine abovecyclobutyl-(5-nitro-pyridin-2-yl)-amine was prepared from2-chloro-5-nitro-pyridine and cyclobutyl amine. LCMS calcd. forC9H11N3O2 (m/e) 193, observed 194 (M+H). This intermediate nitropyridylwas then methylated and reduced toN²-cyclobutyl-N²-methylpyridine-2,5-diamine with a method similar to theone described in the synthesis ofN²-cyclopropyl-N²-methylpyridine-2,5-diamine above. LCMS for C₁₀H₁₅N₃calcd. (m/e) 177, observed 178 (M+H).

Preparation of N²-cyclopropyl-N²-methyl-pyrimidine-2,5-diamine

With a method similar to that used for the preparation ofN²-cyclopropyl-N²-methylpyridine-2,5-diamine above,N²-cyclopropyl-N²-methylpyrimidine-2,5-diamine was prepared from2-chloro-5-nitro-pyrimidine, cyclopropyl amine and methyl iodide. LCMSfor C₈H₁₂N₄ calculated (m/e) 164, observed 165 (M+H).

Preparation of N-(2-methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,N-(2-methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine was prepared from2-chloro-5-nitro-pyrimidine and (2-methoxy-ethyl)-methyl-amine. LCMScalcd for C8H14N4O (m/e) 182, obsd 183 (M+H).

Preparation of 6-((R)-2-methoxymethyl-pyrrolidin-1-yl)-pyridin-3-ylamine

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,6-((R)-2-methoxymethyl-pyrrolidin-1-yl)-pyridin-3-ylamine was preparedfrom 2-chloro-5-nitro-pyridine and (R)-2-methoxymethyl-pyrrolidine. LCMScalcd for C11H17N3O (m/e) 207, obsd 208 (M+H).

Preparation of [(S)-1-(5-amino-pyridin-2-yl)-pyrrolidin-2-yl]-methanol

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,[(S)-1-(5-amino-pyridin-2-yl)-pyrrolidin-2-yl]-methanol was preparedfrom 2-chloro-5-nitro-pyridine and (S)-1-pyrrolidin-2-yl-methanol. LCMScalcd for C10H15N3O (m/e) 193, obsd 194 (M+H).

Preparation of 1-(5-amino-pyridin-2-yl)-pyrrolidin-3-ol

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,1-(5-amino-pyridin-2-yl)-pyrrolidin-3-ol was prepared from2-chloro-5-nitro-pyridine and pyrrolidin-3-ol. LCMS calcd for C9H13N3O(m/e) 179, obsd 180 (M+H).

Preparation of 5′-amino-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-3-ol

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,5′-amino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3-ol was prepared from2-chloro-5-nitro-pyridine and piperidin-3-ol. LCMS calcd for C10H15N3O(m/e) 193, obsd 194 (M+H).

Preparation of 5′-amino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,5′-amino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol was prepared from2-chloro-5-nitro-pyridine and piperidin-4-ol. LCMS calcd for C10H15N3O(m/e) 193, obsd 194 (M+H).

Preparation of (S)-2-(5-Amino-pyrimidin-2-ylamino)-propan-1-ol

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,(S)-2-(5-amino-pyrimidin-2-ylamino)-propan-1-ol was prepared from2-chloro-5-nitro-pyrimidine and 2-amino-propan-1-ol. LCMS calcd forC7H12N4O (m/e) 168, obsd 169 (M+H).

Preparation of (S)-1-(5-amino-pyridin-2-yl)-pyrrolidin-3-ol

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,1-(5-amino-pyridin-2-yl)-pyrrolidin-3-ol was prepared from2-chloro-5-nitro-pyridine and (S)-pyrrolidin-3-ol. LCMS calcd forC9H13N3O (m/e) 179, obsd 180 (M+H).

Preparation of 2-(5-amino-pyridin-2-ylamino)-2-methyl-propan-1-ol

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,2-(5-amino-pyridin-2-ylamino)-2-methyl-propan-1-ol was prepared from2-chloro-5-nitro-pyridine and 2-amino-2-methyl-propan-1-ol. LCMS calcdfor C9H15N3O (m/e) 181, obsd 182 (M+H).

Preparation of [(5-amino-pyridin-2-yl)-methyl-amino]-acetic acid methylester

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,[(5-amino-pyridin-2-yl)-methyl-amino]acetic acid methyl ester wasprepared from 2-chloro-5-nitro-pyridine and methylamino-acetic acidmethyl ester (reaction was heated up to 100° C. in DMF). LCMS calcd forC9H13N3O2 (m/e) 195, obsd 196 (M+H).

Preparation of2-[(5-amino-pyridin-2-yl)-methyl-amino]-N,N-dimethyl-acetamide

With a procedure similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,2-[(5-amino-pyridin-2-yl)-methyl-amino]-N,N-dimethyl-acetamide wasprepared from 2-chloro-5-nitro-pyridin andN,N-dimethyl-2-methylamino-acetamide. Red oil. LCMS calcd for C10H16N4O(m/e) 208, obsd 209 (M+H).

Preparation of 5-morpholin-4-yl-thiazol-2-ylamine

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,5-morpholin-4-yl-thiazol-2-ylamine was prepared from5-bromo-2-nitro-thiazole and morpholine. LCMS calcd for C7H11N3OS (m/e)185, obsd 186 (M+H).

Preparation of N⁵-(2-methoxy-ethyl)-N⁵-methyl-thiazole-2,5-diamine

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,N⁵-(2-methoxy-ethyl)-N⁵-methyl-thiazole-2,5-diamine was prepared from5-bromo-2-nitro-thiazole and (2-methoxy-ethyl)-methyl-amine. LCMS calcdfor C7H13N3OS (m/e) 187, obsd 188 (M+H).

Preparation of N-(5-amino-pyridin-2-yl)-N-methyl-acetamide

A solution of 2-bromo-5-nitro-pyridine (4 g, 19.7 mmol) and methylamine(2 M in THF, 15 mL, 30 mmol) in methylene chloride (40 mL) was heated at50 degrees overnight. After cooling to room temperature, the reactionmixture was concentrated to give methyl-(5-nitro-pyridin-2-yl)-aminethat was used in the following step without purification. Aceticanhydride (9.3 mL, 98.5 mmol) was added to the solution ofmethyl-(5-nitro-pyridin-2-yl)-amine (3.01 g, 19.7 mmol), pyridine (24mL, 197 mmol), and a catalytic amount of 4-dimethylamino-pyridine (DMAP)in methylene chloride (40 mL). The resulted mixture was heated at 90degrees for overnight. After the reaction was complete, solvent wasremoved, and then ethyl acetate was added. The ethyl acetate solutionwas extracted three times with water. Organic layers were combined,washed with brine, dried over sodium sulfate, filtered, and concentratedin vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 50%ethyl acetate in hexane for 20 min) gaveN-methyl-N-(5-nitro-pyridin-2-yl)-acetamide.

Hydrogenation reaction of N-methyl-N-(5-nitro-pyridin-2-yl)-acetamide inmethanol in presence of a catalytic amount of palladium on carbon wascarried out at room temperature with a pressure of 50 psi overnight.After the reaction, the reaction mixture was filtered through a plug ofcelite. The filtrate was collect and concentrated. Flash chromatography(50 g diol column) gave N-(5-amino-pyridin-2-yl)-N-methyl-acetamide.LCMS calcd for C8H11N3O (m/e) 165, obsd 166 (M+H).

Preparation of N-(5-amino-pyridin-2-yl)-N-methyl-propionamide

With a method similar to that used for the preparation ofN-(5-amino-pyridin-2-yl)-N-methyl-acetamide above,N-(5-amino-pyridin-2-yl)-N-methyl-propionamide was prepared frommethyl-(5-nitro-pyridin-2-yl)-amine and propionic anhydride. LCMS calcdfor C9H13N3O (m/e) 179, obsd 180 (M+H).

Preparation of cyclopropanecarboxylic acid(5-amino-pyridin-2-yl)-methyl-amide

With a method similar to that used for the preparation ofN-(5-amino-pyridin-2-yl)-N-methyl-acetamide above,cyclopropanecarboxylic acid (5-amino-pyridin-2-yl)-methyl-amide wasprepared from methyl-(5-nitro-pyridin-2-yl)-amine andcyclopropanecarbonyl chloride. The crude product after reducing thenitro group was directly used in the next step without furtherpurification.

Preparation of N-(5-amino-pyridin-2-yl)-2-methoxy-N-methyl-acetamide

With a method similar to that used for the preparation ofN-(5-amino-pyridin-2-yl)-N-methyl-acetamide above,N-(5-amino-pyridin-2-yl)-2-methoxy-N-methyl-acetamide was prepared frommethyl-(5-nitro-pyridin-2-yl)-amine and methoxy-acetyl chloride. LCMScalcd for C9H13N3O2 (m/e) 195, obsd 196 (M+H).

Preparation of (S)-2-(5-amino-pyridin-2-ylamino)-propan-1-ol

With a method similar to that used for the preparation of6-morpholin-4-yl-pyridin-3-ylamine above,(S)-2-(5-amino-pyridin-2-ylamino)-propan-1-ol was prepared from(S)-2-(5-nitro-pyridin-2-ylamino)-propan-1-ol (commercially availablefrom TCI-EP). LCMS calcd for C8H13N3O (m/e) 167, obsd 168 (M+H).

Preparation of 6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-ylamine

To a solution of 1-(5-nitro-pyridin-2-yl)-pyrrolidin-3-ol (120 mg, 0.57mmol) in 5 mL of DMF was added 10 equivalent of sodium hydride (228 mg,5.7 mmol, 60% in mineral oil). The mixture was stirred at 23° C. for 15min followed by the addition of 10 equivalent of iodomethane (355 uL,5.7 mmol). The reaction was continually stirred for 2 h and thenextracted with ethyl acetate and water. The organic phase was dried andsolvent was evaporated. The residue was purified on a flashchromatography column with EtOAc/hexanes to afford2-(3-methoxy-pyrrolidin-1-yl)-5-nitro-pyridine. LRMS calcd forC10H13N3O3 (m/e) 223, obsd 224 (M+H).

This nitro compound was dissolved in 10 mL of EtOAc, and treated with100 mg of 10% palladium on carbon. The reaction was shaken under 50 psiof H₂ overnight. The reaction was filtered through a celite pad, and thefiltrate was concentrated to afford6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-ylamine, which was used directlyin the next step without further purification. LRMS calcd for C10H15N3O(m/e) 193, obsd 194 (M+H).

Preparation of3-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ylamine

With a method similar to that used for the preparation of6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-ylamine above,3-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ylamine wasprepared from 5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3-ol andiodomethane. LCMS calcd for C11H17N3O (m/e) 207, obsd 208 (M+H).

Preparation ofN²-((S)-2-methoxy-1-methyl-ethyl)-N²-methyl-pyridine-2,5-diamine

With a method similar to that used for the preparation of6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-ylamine above,N²-((S)-2-methoxy-1-methyl-ethyl)-N²-methyl-pyridine-2,5-diamine wasprepared from (S)-2-(5-amino-pyridin-2-ylamino)-propan-1-ol andiodomethane. LCMS calcd for C10H17N3O (m/e) 195, obsd 196 (M+H).

Preparation ofN²-(2-cyclopropylmethoxy-ethyl)-N²-methyl-pyridine-2,5-diamine

With a method similar to that used for the preparation of6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-ylamine above,N²-(2-cyclopropylmethoxy-ethyl)-N²-methyl-pyridine-2,5-diamine wasprepared from 2-[methyl-(5-nitro-pyridin-2-yl)-amino]-ethanol andbromomethyl-cyclopropane. LCMS calcd for C12H19N3O (m/e) 221, obsd 222(M+H).

Preparation of (S)-2-N-(tetrahydrofuran-3-yl)-2,5-diaminopyridine

The (S)-3-aminotetrahydrofuran was prepared as a tosylate salt accordingto the procedure described in literature (Journal of the ChemicalSociety, Chemical Communication 6, 474-475, 1987). (L)-methionine wasprotected as N-trityl-(L)-methionine and the carboxylic acid was reducedto alcohol. The resulting N-tritylmethioninol was methylated to form asulfonium salt which was cyclized to form(S)—N-trityl-3-aminotetrahydrofuran. Final deprotection with p-toluenesulfonic acid in methanol provided (S)-3-aminotetrahydrofuan tosylate asa white solid.

To a mixture of 2-chloro-5-nitropyridine (190 mg, 1.2 mmol) and(S)-3-aminotetrahydrofuran tosylate (305 mg, 1.18 mmol) in DMF (5 mL)was added potassium carbonate (340 mg, 2.46 mmol) and triethyl amine(0.17 mL, 1.22 mmol). The mixture was heated at 65° C. overnight andsolvents were evaporated. The residue was dissolved in ether andextracted with brine. Solvents were evaporated and the oily residue waspurified by flash column chromatography using ethyl acetate and hexanes(10% to 40% ethyl acetate) to give(S)-2-(N-tetrahydrofuran)amino-5-nitro-pyridine as a yellowish oil (180mg, 73%). [α]_(D)=+9.76 (0.675, CHCl₃). LCMS calcd for C9H11N3O3 m/e209.2, obsd 210.1 (M+H). The nitro compound (170 mg, 0.81 mmol) washydrogenated in methanol with catalytic amount of 5% palladium on carbon(35 mg) at 40 psi for 2 hrs. The mixture was filtered and solvents wereevaporated to give the desired compound as an oil (139 mg). MS calcd forC9H13N3O m/e 179.2, obsd 180.0 (M+H).

Preparation of 2-N-(tetrahydrofuran-3-yl)-2,5-diaminopyridine

This compound was prepared with the same method described for thepreparation of (S)-2-N-(tetrahydrofuran-3-yl)-2,5-diaminopyridine byusing 2-chloro-5-nitro-pyridine and racemic 3-aminotetrahydrofuran whichwas synthesized through a Curtius rearrangement oftetrahydrofuran-3-carboxylic acid. LCMS calcd for C9H13N3O m/e 179.2,obsd 180.0 (M+H).

Preparation of 2-N-(tetrahydropyran-4-yl)-2,5-diaminopyridine

This compound was prepared with the same method described before byusing 4-aminotetrahydropyran and 2-chloro-5-nitro-pyridine. LCMS calcdfor C10H15N3O m/e 193.2, obsd 194.1 (ES, M+H).

Preparation of (R)-2-N-(1-phenylethyl)-2,5-diaminopyridine

This compound was prepared with the same method described before byusing (R)-(α)-methylbenzylamine and 2-chloro-5-nitropyridine to give(R)-2-N-(1-phenylethyl)-2-amino-5-nitro-pyridine. LCMS calcd forC13H13N3O2 m/e 243.2, obsd 244.1 (ES, M+H). The nitro compound wasreduced under hydrogenation condition as described before to give(R)-2-N-(1-phenylethyl)-2,5-diaminopyridine.

Preparation of N-(2-methoxy-1-methylethyl)-2,5-diaminopyridine

This compound was prepared with the same method described before byusing 2-methoxy-1-methylethylamine and 2-chloro-5-nitro-pyridine to giveN-(2-methoxy-1-methylethyl)-2-amino-5-nitro-pyridine. LCMS calcd forC9H13N3O3 m/e 211.22, obsd 210.2 (AP, M−H). The nitro compound washydrogenated under the same condition described before to giveN²-(2-methoxy-1-methylethyl)-2,5-diaminopyridine.

Preparation of N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol

To a solution of 2-chloro-5-nitro-pyrimidine (638 mg, 4 mmol) in THF (15mL) cooled to 0° C. was added 3-hydroxypyrrolidine (392 mg, 4.5 mmol)and triethylamine (1.2 mL). The mixture was stirred at room temperatureovernight. Solids were filtered out and the solution was concentrated.The residue was dissolved in ethyl acetate and extracted with water.Organic layer was washed with dilute aqueous citric acid solution. Afterthe evaporation of solvents, the residue was treated with ether and theyellow solid was filtered to giveN-(5-nitro-pyrimidin-2-yl)-pyrrolidin-3-ol (570 mg). LCMS calcd forC8H10N4O3 m/e 210.19, obsd 211.0 (ES, M+H). Hydrogenation of the nitrocompound, as above, provided N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol.

Preparation of (R)—N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol

This compound was prepared with the same method described before using(R)-3-hydroxypyrrolidine and 2-chloro-5-nitropyrimidine to give(R)—N-(5-nitro-pyrimidin-2-yl)-pyrrolidin-3-ol. LCMS calcd for C8H10N4O3m/e 210.19, obsd 211.0 (ES, M+H). Hydrogenation of the nitro compound,as above, provided (R)—N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol.

Preparation of (S)—N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol

This compound was prepared with the same method described before using(S)-3-hydroxypyrrolidine and 2-chloro-5-nitro-pyrimidine to give(S)—N-(5-nitropyrimidin-2-yl)-pyrrolidin-3-ol. LCMS calcd for C8H10N4O3m/e 210.19, obsd 211 (ES, M+H). Hydrogenation of the nitro compound, asabove, provided (S)—N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol.

Preparation of 3-amino-6-(3,3-difluoroazetidin-1-yl)pyridine

The 2-chloro-5-nitro-pyridine (317 mg, 2 mmol) and 3,3-difluoroazetidinehydrochloride (259 mg, 2 mmol) was mixed in 8 mL of THF.Disiopropylethylamine (1.4 mL) was added and the mixture was heated in amicrowave at 120° C. for 20 minutes. After cooling to room temperature,the solid was filtered and the filtrate was distributed between ethylacetate and water. The organic layers were evaporated and the solidmaterial was triturated with methanol. The resulting solid was filteredto give 5-nitro-2-(3,3-difluoroazetidin-1-yl)pyridine. LCMS calcd forC8H7F2N3O2 m/e 215.16, obsd 216.1 (ES, M+H). Hydrogenation of the nitrocompound, as above, provided3-amino-6-(3,3-difluoroazetidin-1-yl)pyridine.

Preparation of N²-methyl-N²-(2,2,2-trifluoro-ethyl)-pyridine-2,5-diamine

A mixture of 2-chloro-5-nitro-pyridine (500 mg, 3.15 mmol),2,2,2-trifluoro-ethylamine (940 mg, 9.45 mmol) andN,N-diisopropylethylamine (1.64 mL, 9.45 mmol) in1-methyl-pyrrolidin-2-one (10 mL) in a sealed tube was heated bymicrowave at 200° C. for 10 minutes. The reaction mixture was evaporatedto dryness and purified by silica gel chromatography (Isco 120 g column,40% ethyl acetate/hexanes) to give(5-nitro-pyridin-2-yl)-(2,2,2-trifluoro-ethyl)-amine (300 mg, 43%) as ayellow solid. LCMS calcd for C7H6F3N3O2 (m/e) 221, obsd 222 (M+H). TheNMR spectrum obtained on the sample is compatible with its structure.

A mixture of (5-nitro-pyridin-2-yl)-(2,2,2-trifluoro-ethyl)-amine (230mg, 1.04 mmol), cesium carbonate (730 mg, 2.07 mmol) and iodomethane(0.59 mL, 4.18 mmol) in DMF (4 mL) was heated in a sealed tube at 50° C.for 3 hr. The reaction mixture was evaporated to dryness and the crudewas partitioned between methylene chloride and water. The organic layerwas dried over magnesium sulfate, filtered and concentrated to givemethyl-(5-nitro-pyridin-2-yl)-(2,2,2-trifluoro-ethyl)-amine (270 mg,crude) as a brown solid, which was directly used in the next stepreaction without further purification. LCMS calcd for C8H8F3N3O2 (m/e)235, obsd 236 (M+H).

A solution ofmethyl-(5-nitro-pyridin-2-yl)-(2,2,2-trifluoro-ethyl)-amine (80 mg, 0.34mmol) in ethanol (10 mL) in the presence of 10% palladium on carbon (10mg) was shaken under hydrogen with a pressure of 50 psi at roomtemperature for 2 hours. After the reaction was complete, the reactionmixture was filtered through a plug of celite and the filtration pad waswashed with ethanol. The organic layers were combined and concentratedto give N²-methyl-N²-(2,2,2-trifluoro-ethyl)-pyridine-2,5-diamine (70mg, crude) as a brown oil, which was directly used in the next stepwithout further purification. LCMS calcd for C8H10F3N3 (m/e) 205, obsd206 (M+H).

Preparation of N-methyl-N-(2,2,2-trifluoro-ethyl)-pyrimidine-2,5-diamine

With procedures similar to that used for the preparation ofN²-methyl-N²-(2,2,2-trifluoro-ethyl)-pyridine-2,5-diamine above,N-methyl-N-(2,2,2-trifluoro-ethyl)-pyrimidine-2,5-diamine was preparedfrom 2-chloro-5-nitro-pyrimidine and 2,2,2-trifluoro-ethylamine. LCMScalcd for C7H9F3N4 (m/e) 206, obsd 207 (M+H). The NMR spectrum obtainedon the sample is compatible with its structure.

Preparation of 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid

Lithium bis(trimethylsilyl)amide (1M in THF, 6 mL, 6 mmol) was added to(benzhydrylidene-amino)-acetic acid benzyl ester (1.97 g, 6 mmol) intetrahydrofuran (10 mL) at −78 degrees. The reaction mixture was stirredat this temperature for about 1 hr. Then isobutyryl chloride (0.641 mL,6 mmol) in tetrahydrofuran (5 mL) was slowly added into the abovemixture. The reaction mixture was warmed up to room temperature andcontinued for another 2 hr. After the completion of the above reaction,the reaction mixture was quenched with dilute hydrochloride acid (2 M)and stirred at room temperature for 1 hr. After removal oftetrahydrofuran, the aqueous solution was extracted with ethyl acetatetwice. The collected organic layers were extracted with dilutehydrochloride acid (2M). The combined aqueous solution was concentratedin vacuo to give 2-amino-4-methyl-3-oxo-pentanoic acid benzyl ester acidchloride, which was used in the next step without further purification.Benzoyl chloride (3 mL) was slowly added to mixture of2-amino-4-methyl-3-oxo-pentanoic acid benzyl ester acid chloride (1.63g, 6 mmol) and anhydrous pyridine (20 mL) in dichloromethane (60 mL) atroom temperature. The reaction mixture was stirred at room temperaturefor 1 hr, after which the solvent was removed and water was added. Theresulted mixture was extracted with ethyl acetate three times. Theorganic layers were collected, washed with brine, dried over sodiumsulfate, and concentrate in vacuo. Flash chromatography (Merck silicagel 60, 230-400 mesh, 0-40% ethylacetate in hexane for 20 min) gave2-benzoylamino-4-methyl-3-oxo-pentanoic acid benzyl ester (1.08 g, 53%)as a light yellow solid. LCMS calcd for C20H21NO4 (m/e) 339, obsd 340(M+H).

Mixture of 2-benzoylamino-4-methyl-3-oxo-pentanoic acid benzyl ester(1.08 g, 3 mmol), triphenylphosphine (2.01 g, 8 mmol), and iodine (1.62g, 6.37 mmol) in tetrahydrofuran (60 mL) was cooled to −78 degrees,followed by addition of triethylamine (1.7 mL). The resulted solutionwas stirred at −78 degrees for about 10 min, and then was warmed up toroom temperature. The reaction continued at room temperature for about 1hr. After the reaction, the solvent was removed, and dichloromethane wasadded. The resulted solution was washed in sequence with saturatedsodium bicarbonate, citric acid (0.5 M), and brine, dried over sodiumsulfate, filtered and then concentrated in vacuo. Flash chromatography(Merck silica gel 60, 230-400 mesh, 0-40% ethyl acetate in hexane for 20min) gave 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid benzyl ester(0.84 g, 82%) as a light yellow solid. LCMS calcd for C20H19NO3 (m/e)321, obsd 322 (M+H).

Solution of 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid benzyl ester(830 mg, 2.59 mmol) in a mix of tetrahydrofuran, methanol and water(3:1:1, 10 mL) was treated with lithium hydroxide monohydride (258 mg,6.5 mmol) at room temperature for an hour. After the reaction wascomplete, solvent was removed. To the residue, water and dichloromethanewere added, and white precipitate formed. After filtering off the solid,filtrate was collected and the phases were separated. The pH of theaqueous layer was adjusted to 1˜2 with dilute hydrochloride acid (1N).Then the aqueous layer was extracted with ethyl acetate three times. Theethyl acetate layers were collected, dried over sodium sulfate, andconcentrated in vacuo. Flash chromatography (Merck silica gel 60,230-400 mesh, 0-80% ethyl acetate in hexane for 20 min) gave5-isopropyl-2-phenyl-oxazole-4-carboxylic acid (247 mg, 41%) as a whitesolid. LCMS calcd for C13H13NO3 (m/e) 231, obsd 232 (M+H).

Preparation of 5-ethyl-2-phenyl-oxazole-4-carboxylic acid

With a method similar to that used for the preparation of5-isopropyl-2-phenyl-oxazole-4-carboxylic acid above,5-ethyl-2-phenyl-oxazole-4-carboxylic acid was prepared from(benzhydrylidene-amino)-acetic acid benzyl ester, propionyl chloride andbenzoyl chloride. LCMS calcd for C12H11NO3 (m/e) 217, obsd 218 (M+H).

Preparation of 2-phenyl-5-propyl-oxazole-4-carboxylic acid

With a method similar to that used for the preparation of5-isopropyl-2-phenyl-oxazole-4-carboxylic acid above,2-phenyl-5-propyl-oxazole-4-carboxylic acid was prepared from(benzhydrylidene-amino)-acetic acid benzyl ester, butyryl chloride andbenzoyl chloride. LCMS calcd for C13H13NO3 (m/e) 231, obsd 232 (M+H).

Preparation of 2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid

With a method similar to that used for the preparation of5-isopropyl-2-phenyl-oxazole-4-carboxylic acid above,2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid was prepared from(benzhydrylidene-amino)-acetic acid benzyl ester, butyryl chloride and2-chloro-benzoyl chloride. LCMS calcd for C13H12ClNO3 (m/e) 265, obsd266 (M+H).

Preparation of 2-(2-bromo-phenyl)-5-propyl-oxazole-4-carboxylic acid

With a method similar to that used for the preparation of5-isopropyl-2-phenyl-oxazole-4-carboxylic acid above,2-(2-bromo-phenyl)-5-propyl-oxazole-4-carboxylic acid was prepared from(benzhydrylidene-amino)-acetic acid benzyl ester, butyryl chloride and2-bromo-benzoyl chloride. LCMS calcd for C13H12BrNO3 (m/e) 310, obsd 311(M+H).

Preparation of 5-propyl-2-o-tolyl-oxazole-4-carboxylic acid

With a method similar to that used for the preparation of5-isopropyl-2-phenyl-oxazole-4-carboxylic acid above,5-propyl-2-o-tolyl-oxazole-4-carboxylic acid was prepared from(benzhydrylidene-amino)-acetic acid benzyl ester, butyryl chloride and2-methyl-benzoyl chloride. LCMS calcd for C14H15NO3 (m/e) 245, obsd 246(M+H).

Preparation of 2-cyclohexyl-5-propyl-oxazole-4-carboxylic acid

With a method similar to that used for the preparation of5-isopropyl-2-phenyl-oxazole-4-carboxylic acid above,2-cyclohexyl-5-propyl-oxazole-4-carboxylic acid was prepared from(benzhydrylidene-amino)-acetic acid benzyl ester, butyryl chloride andcyclohexanecarbonyl chloride. LCMS calcd for C13H19NO3 (m/e) 237, obsd238 (M+H).

Preparation of 5-chloro-2-phenyl-oxazole-4-carboxylic acid

A mixture of phenylboronic acid (729 mg, 5.98 mmol),2-chloro-oxazole-4-carboxylic acid ethyl ester (prepared according tothe procedures described in Org. Lett. 2002, 4 (17), 2905 and J. Med.Chem. 1971, 14, 1075) (1.0 g, 5.70 mmol), Pd[PPh₃]₄ (329 mg, 0.285mmol), and sodium carbonate (2M, 2 mL) in ethylene glycol dimethyl ether(10 mL) were heated at 90 degrees overnight. After cooling the reaction,solvent was removed to give the crude residue. Flash chromatography(Merck silica gel 60, 230-400 mesh, 5-45% ethyl acetate in hexane for 35min) gave 2-phenyl-oxazole-4-carboxylic acid ethyl ester (1.03 g, 83%)as colorless oil. LCMS calcd for C12H11NO3 (m/e) 217, obsd 218 (M+H).

Mixture of 2-phenyl-oxazole-4-carboxylic acid ethyl ester (217 mg, 1mmol), 1-chloro-pyrrolidine-2,5-dione (400 mg, 3 mmol) and two drops ofsulfuric acid in chloroform (10 mL) was heated at 90 degrees forovernight. After the reaction was complete, solvent was evaporated. Tothe residue, water was added, and then the mixture was extracted withethyl acetate twice. The organic layers were collected, combined, washedwith saturated sodium bicarbonate, dried over sodium sulfate, filtered,and concentrated in vacuo. Flash chromatography (Merck silica gel 60,230-400 mesh, 5-40% ethyl acetate in hexane for 30 min) gave5-chloro-2-phenyl-oxazole-4-carboxylic acid ethyl ester (95 mg, 37%) asa white solid. LCMS calcd for C12H10ClNO3 (m/e) 251, obsd 252 (M+H).

Solution of 5-chloro-2-phenyl-oxazole-4-carboxylic acid ethyl ester (92mg, 0.37 mmol) in a mixture solution of tetrahydrofuran, methanol andwater (3:1:1, 5 mL) was treated with lithium hydroxide monohydride (44mg, 1.1 mmol) at room temperature for two hours. After the reaction wascomplete, solvent was evaporated. To the residue, water was added, andpH value of the aqueous layer was adjusted to ˜1-2 by addition of dilutehydrochloride acid (1N). The white precipitation was collected bycentrifugation to give 5-chloro-2-phenyl-oxazole-4-carboxylic acid (73mg, 88%). LCMS calcd for C10H6ClNO3 (m/e) 223, obsd 224 (M+H).

Preparation of 5-bromo-2-phenyl-oxazole-4-carboxylic acid

With a method similar to that used for the preparation of5-chloro-2-phenyl-oxazole-4-carboxylic acid above,5-bromo-2-phenyl-oxazole-4-carboxylic acid was prepared from2-phenyl-oxazole-4-carboxylic acid ethyl ester,1-bromo-pyrrolidine-2,5-dione. LCMS calcd for C10H6BrNO3 (m/e) 268, obsd269 (M+H).

Preparation of 4-phenyl-thiazole-2-carboxylic acid

4-Phenyl-thiazole-2-carboxylic acid ethyl ester, commercially availablefrom Pharma Core, (1.0 g, 4.28 mmol) in a mixture solution oftetrahydrofuran, methanol and Water (3:1:1, 10 mL) was treated withlithium hydroxide monohydride (514 mg, 12.8 mmol) at room temperaturefor three hours. After the reaction was complete, solvent wasevaporated. To the residue, water was added, and pH of the resultingsolution was adjusted to ˜1-2 by addition of dilute hydrochloride acid(1N). The white precipitation was collected by centrifugation andfurther washed with water to give 4-phenyl-thiazole-2-carboxylic acid(473 mg, 54%). LCMS calcd for C10H7NO2S (m/e) 205, obsd 206 (M+H).

Preparation of(methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-aceticacid

From(methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-aceticacid methyl ester:(methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-aceticacid. LCMS calcd for C19H15F3N4O4 (m/e) 420, obsd 421 (M+H).

Preparation of 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester

This compound was prepared according to the procedures described in Int.J Peptide Protein Res. 1989, 33, 353, and J. Chem. Soc., Chem. Commun.1995, 2335. 2-Amino-butyric acid (3.87 g, 37.5 mmol) was suspended in 90mL of dichloromethane, and treated with chloro-trimethyl-silane (9.6 mL,75 mmol). The mixture was refluxed for 1 h and cooled in an ice bath.Diisopropylethylamine (11.3 mL, 65 mmol) and 2-chloro-benzoyl chloride(4.3 mL, 35.6 mmol) were added. The solution was stirred with coolingfor 20 min and then warmed up to room temperature for 1.5 h. The mixturewas concentrated and then distributed between ether and diluted NaHCO₃solution. The phases were separated. The aqueous layer was extractedwith ether and the ether layer was back washed with water. The combinedaqueous layers were acidified to pH 2 with 1N HCl and extracted withethyl acetate three times. The combined ethyl acetate layers were driedover sodium sulfate, filtered and concentrated to give2-(2-chloro-benzoylamino)-butyric acid as an off-white solid (7.0 g, 77%yield), which was used directly in the next step without furtherpurification. LCMS calcd for C11H12ClNO3 (m/e) 241, obsd 242 (M+H).

To a stirred slurry of 2-(2-chloro-benzoylamino)-butyric acid (2.84 g,11.8 mmol) in 60 mL of anhydrous tetrahydro furan, was added oxalylchloride (10.1 mL, 118 mmol). The mixture was stirred at 50° C.overnight and then the solvent was evaporated in vacuo. The oily residuewas treated with toluene and evaporated to remove trace of oxalylchloride. The residue was then cooled in an ice bath and triethylamine(3.4 mL, 23.6 mmol) was added followed by the addition of1-hydroxy-pyrrolidine-2,5-dione. The reaction mixture was stirred at 50°C. overnight before the solvent was removed in vacuo. The residue wasthen purified by flash chromatography (Merck silica gel 60, 230-400mesh, 5-60% ethyl acetate in hexane for 25 min) to give2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester (997 mg, 25% yield) as a light yellowsolid. LCMS calcd for C16H13ClN2O5 (m/e) 348, obsd 349 (M+H).

Preparation of 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester

With a method similar to that used for the preparation of2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester above,2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester was prepared from DL-norvaline and2-chloro-benzoyl chloride. LCMS calcd for C17H15ClN2O5 (m/e) 362, obsd363 (M+H).

Preparation of 4-methyl-2-phenyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester

With a method similar to that used for the preparation of2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester above,4-methyl-2-phenyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-ylester was prepared from DL-alanine and benzoyl chloride. LCMS calcd forC15H12N2O5 (m/e) 300, obsd 301 (M+H).

Preparation of 4-methyl-2-o-tolyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester

With a method similar to that used for the preparation of2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester above,4-methyl-2-o-tolyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-ylester was prepared from DL-alanine and 2-methyl-benzoyl chloride. LCMScalcd for C16H14N2O5 (m/e) 314, obsd 315 (M+H).

Preparation of 4-propyl-2-o-tolyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester

With a method similar to that used for the preparation of2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester above,4-propyl-2-o-tolyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-ylester was prepared from DL-norvaline and 2-methyl-benzoyl chloride. LCMScalcd for C18H18N2O5 (m/e) 342, obsd 343 (M+H).

Preparation of 4-(2-methylsulfanyl-ethyl)-2-phenyl-oxazole-5-carboxylicacid 2,5-dioxo-pyrrolidin-1-yl ester

With a method similar to that used for the preparation of2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester above,4-(2-methylsulfanyl-ethyl)-2-phenyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester was prepared from DL-methionine andbenzoyl chloride. LCMS calcd for C17H16N2O5S (m/e) 360, obsd 361 (M+H).

Preparation of 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester

With a method similar to that used for the preparation of2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester above,2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester was prepared from DL-norvaline and2-bromo-benzoyl chloride. LCMS calcd for C17H15BrN2O5 (m/e) 407, obsd408 (M+H).

Preparation of 2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester

With a method similar to that used for the preparation of2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester above,2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester was prepared from DL-norvaline andcyclohexanecarbonyl chloride. LCMS calcd for C17H22N2O5 (m/e) 334, obsd335 (M+H).

Preparation of 2-phenyl-4-propyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester

With a method similar to that used for the preparation of2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester above,2-phenyl-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-ylester was prepared from DL-norvaline and benzoyl chloride. LCMS calcdfor C17H16N2O5 (m/e) 328, obsd 329 (M+H).

Preparation of2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid

Amino-acetic acid methyl ester (5 g, 40 mmol) was suspended in DMF andtreated with triethylamine (13.9 mL, 100 mmol) and 2-chloro-benzoylchloride (5 mL, 40 mmol). The reaction mixture was stirred at roomtemperature overnight. Water was added to the reaction, and the mixturewas extracted with ethyl acetate three times. The organic layers werecombined and dried over sodium sulfate, filtered and concentrated. Theresidue was purified by flash chromatography using ethyl acetate/hexaneto yield (2-chloro-benzoylamino)-acetic acid methyl ester as a lightyellow solid. LCMS calcd for C10H10ClNO3 (m/e) 227, obsd 228 (M+H).

To a solution of above (2-chloro-benzoylamino)-acetic acid methyl ester(6 g, 26 mmol) in 30 mL of methanol, was added three equivalents oflithium hydroxide hydrate in 10 mL of water. The solution was stirred atroom temperature for 1 hour, concentrated and mixed with water. Citricacid was added until pH of the solution was adjusted to pH 2 to 3. Themixture was extracted with ethyl acetate and the organic layer waswashed with water and brine, dried over MgSO₄, filtered and concentratedto dryness to give (2-chloro-benzoylamino)-acetic acid as a solid. To asolution of (2-chloro-benzoylamino)-acetic acid in 40 mL of acetone at−20° C. was added excess of trifluoroacetic anhydride. The mixture waswarmed up to room temperature and stirred overnight. The solvent wasremoved under vacuum. The residue was poured into 400 mL of water andstirred for 20 min. The solid was filtered out and washed with 2×100 mLof water, and dried under vacuum to give2-(2-chloro-benzoylamino)-4,4,4-trifluoro-3,3-dihydroxy-butyric acid asa red solid. This red solid was suspended in 80 mL of methanol, andheated to reflux for 30 min. The solvent was removed and the mixture waspurified by flash chromatography using ethyl acetate/hexane to give2-(2-chloro-benzoylamino)-4,4,4-trifluoro-3,3-dihydroxy-butyric acidmethyl ester as a light yellow solid. The methyl ester was suspended in100 g of phosphorus oxychloride, and stirred at 80° C. overnight. Thereaction mixture was concentrated to remove excess POCl₃. The remainingoil was diluted with toluene, and poured into a mixture of ice-water.The layers were separated and the organic layer was washed with waterand diluted sodium bicarbonate and then concentrated to dryness. Thesolid was dissolved in 30 mL of methanol and treated with 2.5 equivalentof lithium hydroxide in 30 mL of water, and stirred for 30 min. Methanolwas removed under vacuum, and the mixture was diluted with water. pH ofthe solution was adjusted to about 3 with 12 M hydrochloric acid, andthe mixture was extracted with ethyl acetate. The organic layer wasconcentrated and purified by flash chromatography to give 1.67 g of2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid as alight yellow solid. LCMS calcd for C11H5ClF3NO3 (m/e) 291, obsd 292(M+H).

Preparation of 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylicacid

With a method similar to that used for the preparation of2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid above,2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid wasprepared from 2-bromo-benzoyl chloride, amino-acetic acid methyl esterand trifluoroacetic anhydride. LCMS calcd for C11H5BrF3NO3 (m/e) 336,obsd 337 (M+H).

Preparation of 2-(2-ethyl-phenyl)-5-trifluoromethyl-oxazole-4-carboxylicacid

With a method similar to that used for the preparation of2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid above,2-(2-ethyl-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid wasprepared from 2-ethyl-benzoyl chloride, amino-acetic acid methyl esterand trifluoroacetic anhydride. LCMS calcd for C13H10F3NO3 (m/e) 285,obsd 286 (M+H).

Preparation of2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylicacid

With a method similar to that used for the preparation of2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid above,2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylicacid was prepared from 2-trifluoromethoxy-benzoyl chloride, amino-aceticacid methyl ester and trifluoroacetic anhydride. LCMS calcd forC12H5F6NO4 (m/e) 341, obsd 342 (M+H).

Preparation of2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid

With a method similar to that used for the preparation of2-(2-chloro-phenyl)-5-trifluoromethyloxazole-4-carboxylic acid above,2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid wasprepared from 2-methoxy-benzoyl chloride, amino-acetic acid methyl esterand trifluoroacetic anhydride. LCMS calcd for C12H8F3NO4 (m/e) 287, obsd288 (M+H).

Preparation of 2-cyclohexyl-5-trifluoromethyl-oxazole-4-carboxylic acid

With a method similar to that used for the preparation of2-(2-chloro-phenyl)-5-trifluoromethyloxazole-4-carboxylic acid above,2-cyclohexyl-5-trifluoromethyl-oxazole-4-carboxylic acid was preparedfrom cyclohexanecarbonyl chloride, amino-acetic acid methyl ester andtrifluoroacetic anhydride. LCMS calcd for C11H12F3NO3 (m/e) 263, obsd264 (M+H).

Preparation of 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid

2-Phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid was preparedaccording to the procedure described in Bioorg. Med. Chem. Lett. 2003,13, 1517. A solution of 2-chloro-4,4,4-trifluoro-3-oxo-butyric acidethyl ester (436 mg, 2 mmol) and benzamide (484 mg, 4 mmol) in ethanol(6 mL) in a sealed tube was heated at 120 degrees for 30 h. Aftercooling to room temperature, the reaction mixture was concentrated andpurified by flash chromatography (silica gel 60, 230-400 mesh, 0-80%ethyl acetate in hexane for 25 min) to give4-hydroxy-2-phenyl-4-trifluoromethyl-4,5-dihydro-oxazole-5-carboxylicacid ethyl ester as an off-white solid (229 mg, 38% yield). LCMS calcdfor C13H12F3NO4 (m/e) 303, obsd 304 (M+H). The ester was dehydrated byheating with 2 mL of phosphorus oxychloride at 80 degree overnight. Thereaction mixture was cooled and concentrated. The resulting residue wasmixed with THF and concentrated again to remove remaining POCl₃. Theoily residue was quenched with water and extracted with DCM (2×). Theorganic layer was concentrated. The crude product was purified by flashchromatography (silica gel 60, 230-400 mesh, 0-50% ethyl acetate inhexane for 25 min) to yield2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid ethyl ester as anoff-white solid (160 mg, 75% yield). The ester was hydrolyzed bystirring with lithium hydroxide monohydrate in a mixed solvent of 3:1:1of THF:MeOH:water (3 mL) at RT for 4 h. The reaction was concentratedand water was added. The pH of the solution was adjusted to ˜1-2 with 1N HCl. The white precipitate was collected by centrifugation and washedwith water. After drying under vacuum,2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid was obtained as awhite solid (141 mg, 98% yield. LCMS calcd for C11H6F3NO3 (m/e) 257,obsd 258 (M+H).

Preparation of2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid

With a method similar to that used for the preparation of2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid above,2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid wasprepared from 2-chloro-4,4,4-trifluoro-3-oxo-butyric acid ethyl esterand 2-methoxy-benzamide. LCMS calcd for C12H8F3NO4 (m/e) 287, obsd 288(M+H).

Preparation of2-[2-(2-methoxy-ethoxy)-phenyl]-4-trifluoromethyl-oxazole-5-carboxylicacid

With a method similar to that used for the preparation of2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid above,2-[2-(2-methoxy-ethoxy)-phenyl]-4-trifluoromethyl-oxazole-5-carboxylicacid was prepared from 2-chloro-4,4,4-trifluoro-3-oxo-butyric acid ethylester, 2-hydroxy-benzamide and 1-bromo-2-methoxy-ethane. LCMS calcd forC14H12F3NO5 (m/e) 331, obsd 332 (M+H).

Preparation of 5-cyclohexyl-2-methyl-furan-3-carboxylic acid

A solution of methyl cyclohexylacetate (1.56 g, 10 mmol) in 25 mLanhydrous ether was stirred at −78° C. under argon. DIBAL (1M in hexane,11 mL, 11 mmol) was added dropwise over 45 minutes and the reactionmixture was stirred for an additional 1 hour. A solution of potassiumsodium tartrate tetrahydrate (6 g, 12.2 mmol) in 25 mL water was addedand the mixture stirred at room temperature overnight. After dilutionwith ether, the organic layer was washed with 0.5 N HCl, saturatedsodium bicarbonate and saturated sodium chloride, dried over sodiumsulfate, filtered and concentrated to give cyclohexyl-acetaldehyde (1.17g, 93%).

A solution of the above cyclohexyl-acetaldehyde (1.04 g, 8.25 mmol) andethyl acetoacetate (0.873 mL, 6.85 mmol) in 300 mL ethanol was stirredin an ice bath as piperidine (7.3 uL, 73 umol) in 380 uL ethanol wasadded. The mixture was stirred in the ice bath for 5 hours and placed ina refrigerator for 16 hours. The reaction mixture was diluted with 50 mLether and extracted with saturated sodium chloride (3×30 mL containing 2drops AcOH). The brine layers were back-extracted with ether (2×40 mL).The combined ether layers were washed with brine (30 mL), dried oversodium sulfate, filtered and evaporated to give2-acetyl-4-cyclohexyl-but-2-enoic acid ethyl ester (1.79 g).

A solution of 2-acetyl-4-cyclohexyl-but-2-enoic acid ethyl ester (1.79g, 7.52 mmol) in 40 mL CCl₄ was added to a slurry of NBS (1.338 g, 7.52mmol) in 40 mL CCl₄. The mixture was refluxed under argon for 12 hours,stirred at room temperature for 68 hours and then cooled in an ice bath.The precipitated solid was filtered off and the filtrate was evaporatedto an oil that was purified by short-path distillation (165-185° C., 1mm Hg) yielding 5-cyclohexyl-2-methyl-furan-3-carboxylic acid ethylester (1.36 g, 77%).

A solution of 5-cyclohexyl-2-methyl-furan-3-carboxylic acid ethyl ester(143 mg, 0.605 mmol) and 2N sodium hydroxide (1.5 mL, 3.0 mmol) in 3 mLethanol and 1.5 mL water was heated to reflux for 1 hour. The reactionmixture was cooled, pH adjusted to 1 with 1N HCl and extracted withCH₂Cl₂ (5×40 mL). The combined organic layers were dried over sodiumsulfate, filtered and evaporated to give5-cyclohexyl-2-methyl-furan-3-carboxylic acid (96 mg, 76%).

Preparation of 5-cyclohexyl-2-ethyl-furan-3-carboxylic acid

Similar to the procedure above, except that ethyl 3-oxovalerate was usedinstead of ethyl acetoacetate, 5-cyclohexyl-2-ethyl-furan-3-carboxylicacid was prepared as a powder (49 mg).

Preparation of 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid

A mixture of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester(1.25 g, 6.0 mmol), copper (I) iodide (0.342 g, 1.8 mmol) and potassiumcarbonate (0.58 g, 4.2 mmol) in toluene (6 mL) in a round bottom flaskwas purged with argon. To the reaction mixture was then addediodobenzene (0.81 mL, 7.2 mmol) and racemictrans-N,N′-dimethyl-cyclohexane-1,2-diamine (0.58 mL, 3.6 mmol). Theslurry was heated under Ar in an oil bath at 110° C. for 24 hours. Aftercooling to room temperature, the reaction mixture was diluted with ethylacetate and filtered through a bed of celite. After washing the celitewith ethyl acetate, the fitrates were combined and concentrated to givea crude which was purified by silica gel chromatography (Isco 120 gcolumn, 0 to 30% ethyl acetate/hexanes) to give1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester(1.40 g, 82%) as an off-white solid. The NMR spectrum obtained on thesample is compatible with its structure.

A mixture of 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acidethyl ester (160 mg, 0.56 mmol) and 1N aqueous sodium hydroxide solution(2.3 mL, 2.3 mmol) in methanol (10 mL) was stirred at room temperatureovernight. The reaction mixture was acidified to pH ˜2 with 1N aqueoushydrochloric acid and concentrated to give1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid as an off-whitesolid, which was directly used without further purification. LCMS calcdfor C11H7F3N2O2 (m/e) 256, obsd 257 (M+H).

Preparation of5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid

To a mixture of 5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester (500mg, 2.31 mmol) in N,N-dimethylformamide (30 mL) at 0° C. was addedsodium hydride (60% in mineral oil, 110 mg, 2.75 mmol). The mixture wasstirred at 0° C. for 10 minutes and then at room temperature for 40minutes. After the reaction mixture was re-cooled to 0° C.,2,2,2-trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (500mg, 2.39 mmol) was added dropwise. The mixture was warmed up to roomtemperature and stirred overnight. The reaction was quenched carefullywith ice water and neutralized with 1N aqueous hydrochloric acid. Themixture was extracted with methylene chloride and the organic layer wasdried over sodium sulfate. Filtration and concentration gave a crudewhich was purified by silica gel chromatography (Isco 120 g column, 11%ethyl acetate/hexanes) to give5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid ethylester (360 mg, 52%) as a white solid. The NMR spectrum obtained on thesample is compatible with its structure.

A mixture of 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylicacid ethyl ester (360 mg, 1.21 mmol) and 1N aqueous sodium hydroxidesolution (3.6 mL, 3.6 mmol) in methanol (10 mL) was stirred at roomtemperature overnight. The reaction mixture was acidified to pH ˜2 with1N aqueous hydrochloric acid and concentrated to give5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid as anoff-white solid, which was directly used in the next step reactionwithout further purification. LCMS calcd for C12H9F3N2O2 (m/e) 270, obsd271 (M+H).

Preparation of N-(2-methoxyethyl)-N-methylpyrazine-2,5-diamine

A mixture of methyl 5-chloropyrazine-2-carboxylate (1.0 g, 5.797 mmol)and N-methyl-N-(2-methoxy)ethyl amine (2.0 mL, 18.6 mmol) was heated inan oil bath at 75° C. for 10 minutes. The reaction mixture wasevaporated to dryness and the residue was triturated with dry ether (50mL) to give a solid as methyl5-[N-methyl-N-(2-methoxyethyl)]aminopyrazine-2-carboxylate hydrochloride(1.55 g, 100%). LCMS calcd for C10H15N3O3 (m/e) 225, obsd 226.1 (M+H).

The above solid (1.55 g) was dissolved in methanol (20 mL) and aqueous(1N) sodium hydroxide solution was added (12 mL). The mixture wasstirred at 45° C. for 60 minutes. The reaction mixture was evaporated todryness to give a yellow waxy solid (about 3.0 g) as a sodium5-[N-methyl-N-(2-methoxyethyl)]aminopyrazine-2-carboxylate. LCMS calcdfor C9H13N3O3 (m/e) 211, obsd 212.1 (M+H).

The above crude sodium salt was suspended in DMF (25 mL) anddiphenylphosphorylazide (2.0 mL, 9.3 mmol) was added. The mixture wasstirred at room temperature for 18 hrs to give a clear solution.Solvents were evaporated under vacuum and the residue was extracted withethyl acetate (75 mL) and water (50 mL). The aqueous layer was furtherextracted with ethyl acetate (50 mL). The combined organic layer wasdried over sodium sulfate and solvents were evaporated to give ambercrystals (1.83 g). The crystalline material was dissolved in toluene (20mL) and benzyl alcohol was added. The mixture was stirred at 95° C. for60 minutes. The resulting solution was cooled down to room temperatureand the solution was concentrated to two thirds of the volume untilcrystal material appeared. The solid was filtered and washed withtoluene, then with ether, to give white crystals as5[N-(2-methoxyethyl)-N-methylamino]pyrazine-2-carbamic acid benzyl ester(705 mg, 39%). LCMS calcd for C16H20N4O3 (m/e) 316, obsd 317.2 (M+H).

The above carbamic acid benzyl ester (316 mg, 1.0 mmol) was suspended ina mixture of methanol (25 mL) and THF (5 mL) containing 5% palladium oncarbon (60 mg). The solution was placed under an atmosphere of hydrogen(hydrogen balloon) for one hour. The mixture was filtered through a thinlayer of Celite and the solution was evaporated to give a green oil asN-(2-methoxyethyl)-N-methylpyrazine-2,5-diamine (180 mg, 100%). LCMScalcd for C8H14N4O (m/e) 182, obsd 183.1 (M+H).

Preparation of N-(tetrahydropyran-4-yl)pyrazine-2,5-diamine

A mixture of 4-aminotetrahydropyran (500 mg, 4.94 mmol) and methyl2-chloropryazine-5-carboxylate (770 mg, 4.46 mmol) in DMF (5 mL)containing N,N-diisopropylethylamine (1.0 mL, 5.7 mmol) was stirred at55° C. for 17 hrs. The reaction mixture was concentrated and the residuewas partitioned between ether (25 mL) and hydrochloric acid (1N, 25 mL).The aqueous layer was further extracted with ether (25 mL). Theresulting aqueous layer was first treated with sodium chloride (10 g)and then extracted with methylene chloride (3×50 mL). The organic layerwas washed with brine and dried over sodium sulfate. Solvents wereevaporated to give an oil which slowly crystallized as methyl2-(N-tetrahydropyran-4-yl)-aminopyrazine-5-carboxylate (900 mg, 85%). MScalcd for C11H15N3O3 (m/e) 237, obsd 238.1 (M+H).

The above methyl ester (877 mg, 3.7 mmol) was dissolved in methanol (10mL) and treated with solid sodium hydroxide (300 mg, 7.5 mmol) and water(0.6 mL). The solution was stirred at 50° C. for 60 minutes. Thereaction mixture was evaporated to dryness and the residue was twicedissolved in toluene (2×25 mL) and evaporated to give a solid as asodium salt. This salt was suspended in DMF (15 mL) anddiphenylphosphorylazide (1.1 mL, 5.11 mol) was added. The mixture wasstirred at room temperature overnight to give a clear solution. Solventswere evaporated and the residue was partitioned between ethyl acetate(50 mL) and water (25 mL). The organic layer was dried over sodiumsulfate and solvents were evaporated to give an oil (900 mg). This oilwas treated with benzyl alcohol (0.8 mL, 7.7 mmol) and heated at 95° C.with stirring for 45 minutes. The resulting solid was dissolved in aminimum volume of methylene chloride and loaded to a Biotage flashcolumn eluted with gradient ethyl acetate in hexanes (25% to 100%). Thedesired fractions were concentrated to give yellowish crystals as5-(N-tetrahydropyran-4-yl)aminopyrazine-2-cabamic acid benzyl ester (605mg, 49.7%). MS calcd for C17H20N4O3 (m/e) 328, obsd 329.3 (M+H).

The above carbamic acid methyl ester (200 mg, 0.609 mol) was suspendedin methanol (10 mL) and THF (4 mL) containing 10% palladium on carbon(40 mg). The mixture was placed under an atmosphere of hydrogen(hydrogen balloon) at room temperature for 90 minutes. The mixture wasfiltered through a thin layer of Celite. The filtrate was evaporated todryness go give a yellow solid as5-(N-tetrahydropyran-4-yl)pyrazine-2,5-diamine (120 mg, 100%). MS calcdfor C9H14N4O (m/e) 194, obsd 195.1 (M+H).

Preparation ofN²-[cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamine

To a 20 mL vial containingcis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine, preparedaccording to literature reference (see Chen, et al US 2004/0204427 A1),(580 mg, 2.69 mmol) was added DMF (10 mL), 2-chloro-5-nitro-pyridine(428 mg, 2.69 mmol), and TEA (1.5 mL). The vessel was purged with Ar,sealed, heated to 75° C. for 4.5 hr, cooled to room temperature andallowed to stir over the weekend (60 hr). The reaction mixture washeated again at 75° C. for an additional 6 hr and then allowed to coolto RT overnight (18 hr). The reaction mixture was concentrated andredissolved in DMF (10 mL). 2 eq of K₂CO₃ was added (744 mg) and heatedto 70° C. for 1 hr. The reaction mixture was concentrated, supported onsilica gel, and purified by flash chromatography using an Analogix witha 80 g Redisep silica gel column at 60 mL/min with increasingconcentrations of Et₂O in hexane (0-5 min: 0%, 5-25 min: 0-20%, 25-40min: 30%, 40-65 min: 30-100%). The appropriate fractions were collectedand dried producing a clear oil, 490.8, 54.0% (LCMS 4.23 min, 338 (M+H),calcd. C16H27N3O3Si (m/e) 337, 50-100% ACN in H₂O/HCOOH, C18, APCI). Thenitropyridyl compound was transferred to a PARR vessel with MeOH (10mL), Pd/C (10%) was added and the vessel was pressurized with H₂ at 54psi. After 3 hr the reaction mixture was filtered through a bed ofcelite and concentrated to dryness twice from DCM. The purple blackmaterial was used immediately for amide coupling (LCMS 2.94 min, 308(M+H), calcd. C16H27N3O3Si (m/e) 307, 10-100% ACN in H₂O/HCOOH 0.3%,C18, APCI).

Preparation ofN²-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamine

With a method similar to that used for the preparation ofN²-[cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamineabove,N²-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diaminewas prepared from 2-chloro-5-nitro-pyridine andtrans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl, prepared accordingto literature reference (see Chen, et al US 2004/0204427 A1). (LCMS 3.15min, 308 (M+H), calcd. C16H27N3O3Si (m/e) 307, 0-100% ACN in H₂O/HCOOH0.3%, Echelon C18, ESI).

Preparation ofN²-[(1S,3S)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5diamine

With a method similar to that used for the preparation ofN²-[cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamine,N²-[(1S,3S)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diaminewas prepared fromtrans-(1S,3S)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine and2-chloro-5-nitro-pyridine. LCMS calcd. for C16H29N3OSi (m/e) 307,observed 308 (M+H).

Preparation ofN²-[trans-(1R,3R)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-(5-nitro-pyridin-2-yl)-amine

With a method similar to that used for the preparation ofN²-[cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamine,N²-[(1R,3R)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diaminewas prepared fromtrans-(1R,3R)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine and2-chloro-5-nitro-pyridine. LCMS calcd. for C16H29N3OSi (m/e) 307,observed 308 (M+H).

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-((1S,3S)-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-pyridin-3-yl}-amide

With a method similar to that used for the preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-cyclopentylamino-pyridin-3-yl)-amide above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-((1S,3S)-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-pyridin-3-yl}-amidewas prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acidandN²-[(1S,35)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamine(prepared in situ by the reduction ofN²-[trans-(1S,3S)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-(5-nitro-pyridin-2-yl)-aminefollowing a method similar to that used for the preparation ofN²-cyclopentyl-pyridine-2,5-diamine above). Red solid. LCMS forC₂₇H₃₃F₃N₄O₃Si (m/e) calculated 546, observed 547 (M+H).

Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-((1R,3R)-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-pyridin-3-yl}-amide

With a method similar to that used for the preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-((1S,3S)-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-pyridin-3-yl}-amide above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-((1R,3R)-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-pyridin-3-yl}-amidewas prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acidandN²-[(1R,3R)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamine(prepared in situ by the reduction ofN²-[trans-(1R,3R)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-(5-nitro-pyridin-2-yl)-aminefollowing a method similar to that used for the preparation ofN²-cyclopentyl-pyridine-2,5-diamine above). LCMS for C₂₇H₃₃F₃N₄O₃Si(m/e) calculated 546, observed 547 (M+H).

Preparation of 1-(6-nitropyridine-3-yl)-pyrrolidin-3-ol

A solution of 2-nitro-5-bromopyridine (320 mg, 2.02 mmol) in EtOH (6 mL)was treated with diisopropylethylamine (710 μL, 520 mg, 4.04 mmol) and(S)-3-hydroxypyrrolidinol (350 mg, 4.04 mmol). The mixture was heated ina sealed tube at 85° C. for 21.5 h then cooled and partitioned betweenCH₂Cl₂ and water. The organic layer was dried over Na₂SO₄, filtered andconcentrated and the residue was chromatographed on a silica gel columnwith a 40-100% EtOAc in hexanes to 0-30% THF in EtOAc gradient to affordthe product, as a yellow solid (200 mg, 47% yield). HRMS m/z calcd forC₉H₁₁N₃O₃ [M+H]⁺: 210.0873; Found: 210.0873.

Preparation of 5-(3-(S)-methoxy-pyrrolidin-1-yl)-2-nitro-pyridine

A solution of 5-(3-(S)-hydroxypyrrolidinol)-2-nitropyridine (200 mg,0.96 mmol) in anhydrous THF was treated with MeI (178 μL, 2.88 mmol) andthen NaH, 60% in mineral oil, (57 mg, 1.44 mmol) at room temperature.After stirring overnight at room temperature the reaction mixture waspartitioned between EtOAc and water. The organic layer was dried overNa₂SO₄, filtered and concentrated. Precipitation from CH₂Cl₂ with excessof hexanes afforded the product, as a yellow solid (170 mg, 80% yield).HRMS m/z calcd for C₁₀H₁₁N₃O₃ [M+Na]⁺: 246.0849; Found: 246.0849.

Preparation of (2-methoxyethyl)-methyl-(6-nitropyridin-3-yl)-amine

A solution of 2-nitro-5-bromopyridine (500 mg, 3.15 mmol) in EtOH (15mL) was treated with methoxyethyl-N-methylamine (1.12 g, 12.6 mmol) anddiisopropylethylamine (2.2 mL, 12.6 mmol). The resulting mixture wasthen heated in a sealed tube at 90° C. for 4 days then cooled andpartitioned between EtOAc and water. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was chromatographed on asilica gel column with a 40-100% EtOAc in hexanes gradient to afford theproduct as a thick yellow oil that crystallized slowly upon standing(270 mg, 41% yield). HRMS m/z calcd for C₉H₁₃N₃O₃ [M+Na]⁺: 234.0849;Found: 234.0850.

Preparation of 1-(5-nitro-pyridin-2-yl)-azetidin-3-ol

2-Bromo-5-nitropyridine (406 mg, 2 mmol), 3-hydroxyazetidinehydrochloride (199 mg, 2 mmol), and finely ground potassium carbonate(828 mg, 6 mmol) were heated to 80° C. in 20 mL anhydrous DMF for 5 hrs.The mixture was diluted with EtOAc, extracted with H₂O and dried overMgSO₄. The EtOAc layer was filtered, evaporated to dryness and usedwithout further purification. ES-MS calcd for C₈H₉N₃O₃ (m/e) 195.18,obsd 196.2 (M+H).

Preparation of (2-ethoxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine

(2-Hydroxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (197 mg, 1 mmol)in THF (5 mL) and DMF (2 mL) was stirred with 60% NaH in oil (48 mg, 1.2mmol) for 1 hr. The mixture was cooled and to this was added ethyliodide (120 uL, 1.5 mmol). The reaction was allowed to stir overnight.The mixture was diluted with EtOAc, extracted with H₂O and dried overMgSO₄. The EtOAc layer was filtered, evaporated to dryness and usedwithout further purification. Yield: 155 mg. ES-MS calcd for C10H15N3O3(m/e) 225.25, obsd 225.1 (M+H).

Preparation of 2-(3-methoxy-azetidin-1-yl)-5-nitro-pyridine

1-(5-Nitro-pyridin-2-yl)-azetidin-3-ol (97.5 mg, 0.5 mmol) was treatedwith 60% NaH in oil (40 mg, 1 mmol) and methyl iodide (125 uL, 2 mmol)as above to yield 125 mg of crude product that was used without furtherpurification. ES-MS calcd for C9H11N3O3 (m/e) 209.21, obsd 210 (M+H).

Preparation of sec-butyl-(5-nitro-pyridin-2-yl)-amine

2-Bromo-5-nitropyridine (341 mg, 1.68 mmol), (S)-(+)-sec butylamine (123mg, 1.68 mmol), and finely ground potassium carbonate (707 mg, 5.1 mmol)were heated to 80° C. in 15 mL anhydrous DMF for 3.5 hrs. The mixturewas diluted with EtOAc, extracted with H₂O and dried over MgSO₄. TheEtOAc layer was filtered, evaporated to dryness and purified by flashchromatography to yield 233 mg. ES-MS calcd for C9H13N3O2 (m/e) 195.22,obsd 196.1 (M+H).

Preparation of 2-(3-ethoxy-azetidin-1-yl)-5-nitro-pyridine

1-(5-Nitro-pyridin-2-yl)-azetidin-3-ol (97.5 mg, 0.5 mmol) was treatedwith 60% NaH in oil (60 mg, 1.5 mmol) and ethyl iodide (400 uL, 5 mmol)as above to yield 62 mg of product following purification by flashcromatography. ES-MS calcd for C10H13N3O3 (m/e) 223.23, obsd 224.1(M+H).

Preparation of(2-cyclopropylmethoxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine

(2-Hydroxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (98.5 mg, 0.5mmol) in THF (10 mL) and DMF (2 mL) was stirred with 60% NaH in oil (32mg, 0.8 mmol) for 1 hr. The mixture was cooled and to this was addedbromomethylcyclopropane (0.685 mg, 5 mmol). The reaction mixture wasallowed to stir overnight. The mixture was diluted with EtOAc, extractedwith H₂O and dried over MgSO₄. The EtOAc was filtered, evaporated todryness and used without further purification. Yield: 82 mg. ES-MS calcdfor C12H17N3O3 (m/e) 251.29, obsd 252.1 (M+H).

Preparation of (2-ethoxy-ethyl)-methyl-(5-nitro-pyrimidin-2-yl)-amine

(2-Hydroxy-ethyl)-methyl-(5-nitro-pyrimidin-2-yl)-amine (198 mg, 1 mmol)in THF (15 mL) and DMF (3 mL) was stirred with 60% NaH in oil (60 mg,1.75 mmol) for 1 hr. The mixture was cooled and to this was added ethyliodide. The reaction mixture was allowed to stir overnight. The mixturewas diluted with EtOAc, extracted with H₂O and dried over MgSO₄. TheEtOAc was filtered, evaporated to dryness and used without furtherpurification. Yield: 75 mg. ES-MS calcd for C9H14N4O3 (m/e) 226.24, obsd227 (M+H).

Preparation of [1-(5-nitro-pyridin-2-yl)-azetidin-3-yloxy]-acetic acidtert-butyl ester

1-(5-Nitro-pyridin-2-yl)-azetidin-3-ol (176 mg, 0.9 mmol) was treatedwith 60% NaH in oil (108 mg, 2.7 mmol) and tert-butyl bromoacetate(199.7 uL, 1.35 mmol) as above to yield '210 mg of a yellow solid. ES-MScalcd for C14H19N3O5 (m/e) 309.32, obsd 310.2 (M+H).

Preparation of [1-(5-nitro-pyridin-2-yl)-pyrrolidin-3-yloxy]-acetic acidtert-butyl ester

1-(5-Nitro-pyridin-2-yl)-pyrrolidin-3-ol (340 mg, 1.62 mmol) was treatedwith 60% NaH in oil (130 mg, 3.25 mmol) and tert-butyl bromoacetate (1.2mL, 8.13 mmol) as above to yield 280 mg of a yellow solid followingflash chromatography. ES-MS calcd for C15H21N3O5 (m/e) 323.35, obsd324.1 (M+H).

Preparation of {2-[methyl-(5-nitro-pyridin-2-yl)-amino]-ethoxy}-aceticacid tert-butyl ester

(2-Hydroxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (350 mg, 1.77mmol) in THF (15 mL) and DMF (2 mL) was stirred with 60% NaH in oil (142mg, 4.44 mmol) for 1 hr. The mixture was cooled and to this was addedtert-butyl bromoacetate (1.31 mL, 8.88 mmol). The reaction mixture wasallowed to stir overnight. The mixture was diluted with EtOAc, extractedwith H₂O and dried over MgSO₄. The EtOAc layer was filtered, evaporatedto dryness and yielded 262 mg following flash chromatography. ES-MScalcd for C14H21N3O5 (m/e) 311.34, obsd 312 (M+H).

Preparation of methyl-(3-methyl-butyl)-(5-nitro-pyridin-2-yl)-amine

2-Chloro-5-nitropyridine (158 mg, 1 mmol), N-methylisoamylamine (101 mg,1 mmol), and finely ground potassium carbonate (419 mg, 3 mmol) wereheated to 80° C. in 10 mL anhydrous DMF for 3.5 hrs. The mixture wasdiluted with EtOAc, extracted with H₂O and dried over MgSO₄. The EtOAclayer was filtered, evaporated to dryness to yield 220 mg. ES-MS calcdfor C11H17N3O2 (m/e) 223.28, obsd 224.1 (M+H).

Preparation of 3-[methyl-(5-nitro-pyridin-2-yl)-amino]-propionitrile

2-Chloro-5-nitropyridine (158 mg, 1 mmol), 3-methylamino-propionitrile(84 mg, 1 mmol), and finely ground potassium carbonate (414 mg, 3 mmol)were heated to 80° C. in 10 mL anhydrous DMF for 3.5 hrs. The mixturewas diluted with EtOAc, extracted with H₂O and dried over MgSO₄. TheEtOAc layer was filtered, evaporated to dryness. ES-MS calcd forC9H10N4O2 (m/e) 206.21, obsd 207.1 (M+H).

Preparation of bicyclo[2.2.1]hept-2-yl-(5-nitro-pyridin-2-yl)-amine

2-Chloro-5-nitropyridine (158 mg, 1 mmol), 2-aminonorbornanehydrochloride (147 mg, 1 mmol), and finely ground potassium carbonate(419 mg, 3 mmol) were heated to 80° C. in 10 mL anhydrous DMF for 3.5hrs. The mixture was diluted with EtOAc, extracted with H₂O and driedover MgSO₄. The EtOAc was filtered, evaporated to dryness to yield 220mg. ES-MS calcd for C12H15N3O2 (m/e) 233.21, obsd 234.1 (M+H).

Part II: Examples of Preferred Embodiments Example 1 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide

A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (1.58g, 6.14 mmol), 6-morpholin-4-yl-pyridin-3-ylamine (1.0 g, 5.58 mmol),N-hydroxybenzotriazole (1.27 g, 8.37 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.6 g, 8.37mmol) in anhydrous dichloromethane (20 mL) was stirred at roomtemperature overnight. After the reaction was complete, solvent wasevaporated. The resulted mixture was mixed with water and extractedtwice with ethyl acetate. The organic layers were collected, combined,washed with brine, dried over sodium sulfate, and then concentrated togive a solid. The crude product was purified by flash chromatography(Merck silica gel 60, 230-400 mesh, 0%-100% ethyl acetate in hexane) togave 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide (1.15 g, 50%) as an off-whitesolid. LCMS calcd for C20H17F3N4O3 (m/e) 418, obsd 419 (M+H).

Example 2 Preparation of 2-phenyl-thiazole-4-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide

With a procedure similar to example 1 above,2-phenyl-thiazole-4-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from2-phenyl-thiazole-4-carboxylic acid and6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C19H18N4O2S (m/e)366, obsd 367 (M+H).

Example 3 Preparation of 4-phenyl-thiazole-2-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide

With a procedure similar to example 1 above,4-phenyl-thiazole-2-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from4-phenyl-thiazole-2-carboxylic acid and6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C19H18N4O2S (m/e)366, obsd 367 (M+H).

Example 4 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid (2-morpholin-4-yl-pyrimidin-5-yl)-amide

With a procedure similar to example 1 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(2-morpholin-4-yl-pyrimidin-5-yl)-amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and2-morpholin-4-yl-pyrimidin-5-ylamine. LCMS calcd for C19H16F3N5O3 (m/e)419, obsd 420 (M+H).

Example 5 Preparation of5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide

With a procedure similar to example 1 above,5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid and6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C19H20N6O2 (m/e) 364,obsd 365 (M+H).

Example 6 Preparation of 5-bromo-2-phenyl-oxazole-4-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide

With a procedure similar to example 1 above,5-bromo-2-phenyl-oxazole-4-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from5-bromo-2-phenyl-oxazole-4-carboxylic acid and6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C19H17BrN4O3 (m/e)429, obsd 430 (M+H).

Example 7 Preparation of 5-phenyl-2-trifluoromethyl-furan-3-carboxylicacid (6-morpholin-4-yl-pyridin-3-yl)-amide

With a procedure similar to example 1 above,5-phenyl-2-trifluoromethyl-furan-3-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from5-phenyl-2-trifluoromethyl-furan-3-carboxylic acid andmethyl-(6-morpholin-4-yl-pyridin-3-yl)-amine. LCMS calcd forC21H18F3N3O3 (m/e) 417, obsd 418 (M+H).

Example 8 Preparation of 5-chloro-2-phenyl-oxazole-4-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide

With a procedure similar to example 1 above,5-chloro-2-phenyl-oxazole-4-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from5-chloro-2-phenyl-oxazole-4-carboxylic acid andmethyl-(6-morpholin-4-yl-pyridin-3-yl)-amine. LCMS calcd forC19H17ClN4O3 (m/e) 384, obsd 385 (M+H).

Example 9 Preparation of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 1 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC20H19F3N4O3 (m/e) 420, obsd 421 (M+H).

Example 10 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide

With a procedure similar to example 1 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was preparedfrom 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN-(2-methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine. LCMS calcd forC19H18F3N5O3 (m/e) 421, obsd 422 (M+H).

Example 11 Preparation of(methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-aceticacid methyl ester

With a procedure similar to example 1 above,(methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-aceticacid methyl ester was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and[(5-amino-pyridin-2-yl)-methyl-amino]-acetic acid methyl ester. LCMScalcd for C20H17F3N4O4 (m/e) 434, obsd 435 (M+H).

Example 12 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(methyl-methylcarbamoylmethyl-amino)-pyridin-3-yl]-amide

With a procedure similar to example 1 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(methyl-methylcarbamoylmethyl-amino)-pyridin-3-yl]-amide was preparedfrom(methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-aceticacid and methyl amine. LCMS calcd for C20H18F3N5O3 (m/e) 433, obsd 434(M+H).

Example 13 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(dimethylcarbamoylmethyl-methyl-amino)-pyrdin-3-yl]-amide

With a procedure similar to example 16,2-phenyl-5-trifluorormethyl-oxazole-4-carboxylic acid[6-(dimethylcarbamoylmethyl-methyl-amino)-pyrdin-3-yl]-amide wasprepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and2-[(5-amino-pyridin-2-yl)-methyl-amino]-N,N-dimethyl-acetamide LCMScalcd for C21H20F3N5O3 (m/e) 447.42, obsd 448.16 (M+H).

Example 14 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-thiomorpholin-4-yl-pyridin-3-yl)-amide

With a procedure similar to example 1 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-thiomorpholin-4-yl-pyridin-3-yl)-amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and6-thiomorpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C20H17F3N4O2S(m/e) 434, obsd 435 (M+H).

Example 15 Preparation of 4-methyl-2-phenyl-thiazole-5-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide

With a procedure similar to example 1 above,4-methyl-2-phenyl-thiazole-5-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from4-methyl-2-phenyl-thiazole-5-carboxylic acid and6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C20H20N4O2S (m/e)380, obsd 381 (M+H).

Example 16 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-amide

With a procedure similar to example 1 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-amide wasprepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN-[1-(5-amino-pyridin-2-yl)-pyrrolidin-3-yl]-N-methyl-acetamide. LCMScalcd for C23H22F3N5O3 (m/e) 473, obsd 474 (M+H).

Example 17 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(R)-3-(acetyl-methyl-amino)-pyrrolidin-1-yl]pyridin-3-yl}-amide

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(R)-3-(acetyl-methyl-amino)-pyrrolidin-1-yl]-pyridin-3-yl}-amide wasprepared as a light yellow solid from the corresponding racemic compoundby chiral supercritical fluid chromatography (Daicel AD column, 40%(1:1) EtOH/acetonitrile plus 20 mM ammonium acetate as a modifier).[α]_(D)=−15.2 (MeOH).

Example 18 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(acetyl-methyl-amino)-pyridin-3-yl]-amide

A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (260mg, 1 mmol), N-(5-amino-pyridin-2-yl)-N-methyl-acetamide (165 mg, 1mmol), bromo-tri-pyrrolidino-phosphonium hexafluorophosphate (470 mg, 1mmol), and triethylamine (202 mg, 2 mmol) in anhydrous dichloromethane(5 mL) was stirred at room temperature overnight. After the reaction wascomplete, the solvent and excess triethylamine were removed byevaporation. Flash chromatography (Merck silica gel 60, 230-400 mesh,0%-40% ethyl acetate in hexane for 20 min) gave2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(acetyl-methyl-amino)-pyridin-3-yl]-amide as a yellow solid. LCMScalcd for C19H15F3N4O3 (m/e) 404, obsd 405 (M+H).

Example 19 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(cyclopropanecarbonyl-methyl-amino)-pyridin-3-yl]-amide

With a procedure similar to example 16,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(cyclopropanecarbonyl-methyl-amino)-pyridin-3-yl]-amide was preparedas a white solid from 2-chloro-5-nitro-pyridine and cyclopropanecarboxylic acid (4-amino-phenyl)-methyl-amide. LCMS calcd forC21H17F3N4O3 (m/e) 430, obsd 431 (M+H).

Example 20 Preparation of 5-isopropyl-2-phenyl-oxazole-4-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide

With a procedure similar to example 16 above,5-isopropyl-2-phenyl-oxazole-4-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from5-isopropyl-2-phenyl-oxazole-4-carboxylic acid and6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C22H24N4O3 (m/e) 392,obsd 393 (M+H).

Example 21 Preparation of 5-chloro-2-phenyl-oxazole-4-carboxylic acid[6-(acetyl-methyl-amino)-pyridin-3-yl]-amide

With a procedure similar to example 16 above,5-chloro-2-phenyl-oxazole-4-carboxylic acid[6-(acetyl-methyl-amino)-pyridin-3-yl]-amide was prepared from5-chloro-2-phenyl-oxazole-4-carboxylic acid andN-(5-amino-pyridin-2-yl)-N-methyl-acetamide. LCMS calcd for C18H15ClN4O3(m/e) 370, obsd 371 (M+H).

Example 22 Preparation of 5-ethyl-2-phenyl-oxazole-4-carboxylic acid[6-(acetyl-methyl-amino)-pyridin-3-yl]-amide

With a procedure similar to example 16 above,5-ethyl-2-phenyl-oxazole-4-carboxylic acid[6-(acetyl-methyl-amino)-pyridin-3-yl]-amide was prepared from5-ethyl-2-phenyl-oxazole-4-carboxylic acid andN-(5-amino-pyridin-2-yl)-N-methyl-acetamide. LCMS calcd for C20H20N4O3(m/e) 364, obsd 365 (M+H).

Example 23 Preparation of 5-ethyl-2-phenyl-oxazole-4-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide

With a procedure similar to example 16 above,5-ethyl-2-phenyl-oxazole-4-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from5-ethyl-2-phenyl-oxazole-4-carboxylic acid and6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C21H22N4O3 (m/e) 378,obsd 379 (M+H).

Example 24 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(methyl-propionyl-amino)-pyridin-3-yl]-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(methyl-propionyl-amino)-pyridin-3-yl]-amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN-(5-amino-pyridin-2-yl)-N-methyl-propionamide. LCMS calcd forC20H17F3N4O3 (m/e) 418, obsd 419 (M+H).

Example 25 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-yl]amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and6-(3-methoxy-pyrrolidin-1-yl)-pyridin-3-ylamine. LCMS calcd forC21H19F3N4O3 (m/e) 432, obsd 433 (M+H).

Example 26 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-((S)-3-methoxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-((S)-3-methoxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide was prepared fromthe corresponding racimic compound by chiral supercritical fluidchromatography (Whelk-O1 R,R column, 35% MeOH as a modifier). [α]_(D)=+14.5, (MeOH).

Example 27 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(3-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(3-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide wasprepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and3-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ylamine. LCMS calcdfor C22H21F3N4O3 (m/e) 446, obsd 447 (M+H).

Example 28 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(methyl-propyl-amino)-pyridin-3-yl]-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(methyl-propyl-amino)-pyridin-3-yl]-amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-methyl-N²-propyl-pyridine-2,5-diamine. LCMS calcd for C20H19F3N4O2(m/e) 404, obsd 405 (M+H).

Example 29 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(butyl-methyl-amino)-pyridin-3-yl]-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(butyl-methyl-amino)-pyridin-3-yl]-amide From2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-butyl-N²-methyl-pyridine-2,5-diamine. LCMS calcd for C21H21F3N4O2(m/e) 418, obsd 419 (M+H).

Example 30 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-(3-methoxy-propyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC21H21F3N4O3 (m/e) 434, obsd 435 (M+H).

Example 31 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(3-methoxy-propylamino)-pyridin-3-yl]-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(3-methoxy-propylamino)-pyridin-3-yl]amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-(3-methoxy-propyl)-pyridine-2,5-diamine. LCMS calcd for C20H19F3N4O3(m/e) 420, obsd 421 (M+H).

Example 32 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(2-morpholin-4-yl-thiazol-5-yl)-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(2-morpholin-4-yl-thiazol-5-yl)-amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and2-morpholin-4-yl-thiazol-5-ylamine. LCMS calcd for C18H15F3N4O3S (m/e)424, obsd 425 (M+H).

Example 33 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{2-[(2-methoxy-ethyl)-methyl-amino]-thiazol-5-yl}-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{2-[(2-methoxy-ethyl)-methyl-amino]-thiazol-5-yl}-amide was preparedfrom 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-(2-methoxy-ethyl)-N²-methyl-thiazole-2,5-diamine. LCMS calcd forC18H17F3N4O3S (m/e) 426, obsd 427 (M+H).

Example 34 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-((R)-2-methoxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-((R)-2-methoxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-amide wasprepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and6-((R)-2-methoxymethyl-pyrrolidin-1-yl)-pyridin-3-ylamine. LCMS calcdfor C22H21F3N4O3 (m/e) 446, obsd 447 (M+H).

Example 35 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[ethyl-(2-methoxy-ethyl)-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[ethyl-(2-methoxy-ethyl)-amino]-pyridin-3-yl}-amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-ethyl-N²-(2-methoxy-ethyl)-pyridine-2,5-diamine. LCMS calcd forC21H21F3N4O3 (m/e) 434, obsd 435 (M+H).

Example 36 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(2-methoxy-ethylamino)-pyridin-3-yl]-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(2-methoxy-ethylamino)-pyridin-3-yl]-amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-(2-methoxy-ethyl)-pyridine-2,5-diamine. LCMS calcd for C19H17F3N4O3(m/e) 406, obsd 407 (M+H).

Example 37 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(2-methoxy-ethoxy)-pyridin-3-yl]-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(2-methoxy-ethoxy)-pyridin-3-yl]-amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and6-(2-methoxy-ethoxy)-pyridin-3-ylamine. LCMS calcd for C19H16F3N3O4(m/e) 407, obsd 408 (M+H).

Example 38 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(ethyl-methyl-amino)-pyridin-3-yl]-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(ethyl-methyl-amino)-pyridin-3-yl]amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-ethyl-N²-methyl-pyridine-2,5-diamine. LCMS calcd for C19H17F3N4O2(m/e) 390, obsd 391 (M+H).

Example 39 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-ethylamino-pyridin-3-yl)-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-ethylamino-pyridin-3-yl)-amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-ethyl-pyridine-2,5-diamine. LCMS calcd for C18H15F3N4O2 (m/e) 376,obsd 377 (M+H).

Example 40 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-diethylamino-pyridin-3-yl)-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-diethylamino-pyridin-3-yl)-amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²,N²-diethyl-pyridine-2,5-diamine. LCMS calcd for C20H19F3N4O2 (m/e)404, obsd 405 (M+H).

Example 41 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-dimethylamino-pyridin-3-yl)-amide

With a procedure similar to the example 1 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-dimethylamino-pyridin-3-yl)-amide was prepared from2-phenyl-trifluoromethyl-oxazole-4-carboxylic acid andN²,N²-dimethyl-pyridine-2,5-diamine. LCMS calcd for C18H15F3N4O2 (m/e)376.34 obsd 377.12 (M+H).

Example 42 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(isopropyl-methyl-amino)-pyridin-3-yl]-amide

With a procedure similar to example 1 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(isopropyl-methyl-amino)-pyridin-3-yl]-amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-isopropyl-N²-methyl-pyridine-2,5-diamine. LCMS calcd for C20H19F3N4O2(m/e) 404, obsd 405 (M+H).

Example 43 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-cyclopentylamino-pyridin-3-yl)-amide

A mixture of 2-phenyl-5-(trifluoromethyl)-oxazole-4-carboxylic acid (454mg, 1.77 mmol), CH₂Cl₂ (5 mL), and a catalytic amount of DMF was stirredunder Ar, cooled in an ice bath, and oxalyl chloride (308 μL, 3.53 mmol)was added dropwise into the mixture over 5 min. The mixture wasimmediately allowed to warm to room temperature and after 1.5 hr thereaction was concentrated to dryness. Dichloromethane was added and thesolution was evaporated to dryness again. The white-yellow solid wasre-dissolved in 5 mL of CH₂Cl₂ and added dropwise, under Ar, into a 0°C. solution of cyclopentyl-pyridine-2,5-diamine (448 mg, 2.53 mmol), acatalytic amount of DMAP and triethylamine (602 μL, 4.33 mmol) in 5 mLof CH₂Cl₂. The reaction was allowed to warm to room temperatureovernight then concentrated and the residue was supported onto silicagel, and purified by flash chromatography using the Analogix system witha 40 g Redisep silica gel column with increasing concentrations of EtOAcin hexane (40 mL/min, equilibrate with 0%, 0-5 min: 0%, 5-25 min: 0 to30%, 25-40 min: 30%). The product was tirturated with hexanes six timesand a 10% ether hexane four times, 20 mL total, to afford the product,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-cyclopentylamino-pyridin-3-yl)-amide, as an off white solid (315 mg,50% yield). LCMS for C21H19F3N4O2 calcd. (m/e) 416, observed 417 (M+H).

Example 44 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-cyclohexylamino-pyridin-3-yl)-amide

With a method similar to that used for the preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-cyclopentylamino-pyridin-3-yl)-amide above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-cyclohexylamino-pyridin-3-yl)-amide was prepared from2-phenyl-5-(trifluoromethyl)-oxazole-4-carboxylic acid andN²-cyclohexyl-pyridine-2,5-diamine. After flash column chromatography,as described above, and recrystallization from ether the product wasisolated as a white pink solid. LCMS for C₂₂H₂₁F₃N₄O₂ calculated (m/e)430, observed 431 (M+H).

Example 45 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-cyclopropylamino-pyridin-3-yl)-amide

With a method similar to that used for the preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-cyclopentylamino-pyridin-3-yl)-amide above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-cyclopropylamino-pyridin-3-yl)-amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-cyclopropyl-pyridine-2,5-diamine as a light purple solid. LCMS forC₁₉H₁₅F₃N₄O₂ calculated (m/e) 388, observed 389 (M+H).

Example 46 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(cyclopropyl-methyl-amino]-pyridin-3-yl]-amide

With a method similar to that used for the preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-cyclopentylamino-pyridin-3-yl)-amide above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-cyclopropyl-N²-methyl-pyridine-2,5-diamine as a yellow solid. LCMSfor C₂₀H₁₇F₃N₄O₂ calculated (m/e) 402, observed 403 (M+H).

Example 47 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(cyclobutyl-methyl-amino]-pyridin-3-yl]-amide

With a method similar to that used for the preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-cyclopentylamino-pyridin-3-yl)-amide above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(cyclobutyl-methyl-amino)-pyridin-3-yl]-amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-cyclobutyl-N²-methyl-pyridine-2,5-diamine as a yellow solid. (LCMSfor C₂₁H₁₉F₃N₄O₂ calcd. (m/e) 416, observed 417 (M+H).

Example 48 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(cyclopropyl-methyl-amino]-pyrimidin-3-yl]-amide

With a method similar to that used for the preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-cyclopentylamino-pyridin-3-yl)-amide above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(cyclopropyl-methyl-amino)-pyrimidin-3-yl]-amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-cyclopropyl-N²-methyl-pyrimidine-2,5-diamine as a white light yellowsolid (LCMS for C₁₉H₁₆F₃N₅O₂ calculated (m/e) 403, observed 404 (M+H).

Example 49 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-methoxy-acetyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-methoxy-acetyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN-(5-amino-pyridin-2-yl)-2-methoxy-N-methyl-acetamide. LCMS calcd forC20H17F3N4O4 (m/e) 434, obsd 435 (M+H).

Example 50 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[((S)-2-methoxy-1-methyl-ethyl)-methyl-amino]pyridin-3-yl}-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[((S)-2-methoxy-1-methyl-ethyl)-methyl-amino]-pyridin-3-yl}-amide wasprepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-((S)-2-methoxy-1-methyl-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMScalcd for C21H21F3N4O3 (m/e) 434, obsd 435 (M+H).

Example 51 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid-[6-(2-methoxy-1-methyl-ethylamino)pyridin-3-yl]amide hydrogenchloride

With a method similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid-[6-(2-methoxy-1-methyl-ethylamino)pyridin-3-yl]amide hydrogenchloride was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN-(2-methoxy-1-methyl-ethyl)-2,5-diaminopyridine. The purified oilymaterial from column chromatography was dissolved in ether and treatedwith gaseous hydrogen chloride in ether (3N) to give a white precipitateas a hydrochloride salt. LCMS calcd for the neutral form C20H19F3N4O3m/e 420.39, obsd 421.02 (ES, M+H).

Example 52 Preparation of(R)-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid-[6-(1-phenyl-ethylamino)pyridin-3-yl]amide

With a method similar to example 16 above,(R)-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid-[6-(1-phenyl-ethylamino)pyridin-3-yl]amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and(R)-2-N-(1-phenylethyl)-2,5-diaminopyridine. LCMS calcd for C24H19F3N4O2m/e 452.4, obsd 453.2 (ES, M+H).

Example 53 Preparation of 2-phenyl-5-trifluoromethyloxazole-4-carboxylicacid-[6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl]amide

With a method similar to example 16 above,2-phenyl-5-trifluoromethyloxazole-4-carboxylicacid-[6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl]amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and3-amino-6-(3,3-difluoroazetidin-1-yl)pyridine. LCMS calcd forC19H13F5N4O2 m/e 424.33, obsd 425.0 (ES, M+H).

Example 54 Preparation of 2-phenyl-5-trifluormethyl-oxazole-4-carboxylicacid {6-[methyl-(2,2,2-trifluoro-ethyl)-amino]pyridin-3-yl}-amide

With a procedure similar to example 16 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[methyl-(2,2,2-trifluoro-ethyl)-amino]-pyridin-3-yl}-amide wasprepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-methyl-N²-(2,2,2-trifluoro-ethyl-pyridine-2,5-diamine. LCMS calcd forC19H14F6N4O2 (m/e) 444, obsd 445 (M+H). The NMR spectrum obtained on thesample is compatible with its structure.

Example 55 Preparation of5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid{6-[methyl-(2,2,2-trifluoro-ethyl)-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid{6-[methyl-(2,2,2-trifluoro-ethyl)-amino]-pyridin-3-yl}-amide wasprepared from 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid andN²-methyl-N²-(2,2,2-trifluoro-ethyl)-pyridine-2,5-diamine. LCMS calcdfor C18H17F3N6O (m/e) 390, obsd 391 (M+H). The NMR spectrum obtained onthe sample is compatible with its structure.

Example 56 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{2-[methyl-(2,2,2-trifluoro-ethyl)-amino]-pyrimidin-5-yl}-amide

With a procedure similar to example 16 above,2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{2-[methyl-(2,2,2-trifluoro-ethyl)-amino]-pyrimidin-5-yl}-amide wasprepared from 2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN-Methyl-N-(2,2,2-trifluoro-ethyl)-pyrimidine-2,5-diamine. LCMS calcdfor C18H13F6N5O2 (m/e) 445, obsd 446 (M+H). The NMR spectrum obtained onthe sample is compatible with its structure.

Example 57 Preparation of5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid[6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide

With a procedure similar to example 16 above,5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid[6-(cyclopropyl-methyl-amino)-pyridin-3-yl]amide was prepared from5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid andN²-cyclopropyl-N²-methyl-pyridine-2,5-diamine. LCMS calcd for C19H20N6O(m/e) 348, obsd 349 (M+H).

Example 58 Preparation of 2-methyl-5-phenyl-2H-pyrazole-3-carboxylicacid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-methyl-5-phenyl-2H-pyrazole-3-carboxylic acid (made by hydrolysisof the corresponding commercially available ethyl ester) andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC20H23N5O2 (m/e) 365, obsd 366 (M+H). The NMR spectrum obtained on thesample is compatible with its structure.

Example 59 Preparation of5-(4-methoxy-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,5-(4-methoxy-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 5-(4-methoxy-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid (madeby hydrolysis of the corresponding commercially available ethyl ester)and N²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC21H25N5O₃ (m/e) 395, obsd 396 (M+H). The NMR spectrum obtained on thesample is compatible with its structure.

Example 60 Preparation of5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acidand N²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC21H22F3N5O2 (m/e) 433, obsd 434 (M+H). The NMR spectrum obtained on thesample is compatible with its structure.

Example 61 Preparation of1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC20H20F3N5O2 (m/e) 419, obsd 420 (M+H). The NMR spectrum obtained on thesample is compatible with its structure.

Example 62 Preparation of5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC19H22N6O2 (m/e) 366, obsd 367 (M+H). The NMR spectrum obtained on thesample is compatible with its structure.

Example 63 Preparation of2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC20H18ClF3N4O3 (m/e) 454, obsd 455 (M+H).

Example 64 Preparation of2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide

With a procedure similar to example 16 above,2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C20H16ClF3N4O3 (m/e)452, obsd 453 (M+H).

Example 65 Preparation of2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC20H18BrF3N4O3 (m/e) 499, obsd 500 (M+H).

Example 66 Preparation of2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(ethyl-methyl-amino)-pyridin-3-yl]-amide

With a procedure similar to example 16 above,2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(ethyl-methyl-amino)-pyridin-3-yl]-amide was prepared from2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-ethyl-N²-methyl-pyridine-2,5-diamine. LCMS calcd for C19H16BrF3N4O2(m/e) 469, obsd 470 (M+H).

Example 67 Preparation of2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-cyclopropylmethoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-cyclopropylmethoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide wasprepared from 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylicacid and N²-(2-cyclopropylmethoxy-ethyl)-N²-methyl-pyridine-2,5-diamine.LCMS calcd for C23H22BrF3N4O3 (m/e) 539, obsd 540 (M+H).

Example 68 Preparation of2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid{2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide

With a procedure similar to example 16 above,2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid{2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was preparedfrom 2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-(2-methoxy-ethyl)-N²-methyl-pyrimidine-2,5-diamine. LCMS calcd forC19H17BrF3N5O3 (m/e) 500, obsd 501 (M+H).

Example 69 Preparation of2-(2-ethyl-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,2-(2-ethyl-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-(2-ethyl-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC22H23F3N4O3 (m/e) 448, obsd 449 (M+H).

Example 70 Preparation of2-cyclohexyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,2-cyclohexyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-cyclohexyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC20H25F3N4O3 (m/e) 426, obsd 427 (M+H).

Example 71 Preparation of2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylicacid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylicacid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide wasprepared from2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylicacid and N²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcdfor C21H18F6N4O4 (m/e) 504. obsd 505 (M+H).

Example 72 Preparation of2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylicacid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide

With a procedure similar to example 16 above,2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylicacid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide wasprepared from2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylicacid and N-(2-methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine. LCMS calcdfor C20H17F6N5O4 (m/e) 505. obsd 506 (M+H).

Example 73 Preparation of2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl-methyl-amino]-pyridin-3-yl}-amide was prepared from2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC21H21F3N4O4 (m/e) 504. obsd 505 (M+H).

Example 74 Preparation of2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid{2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide

With a procedure similar to example 16 above,2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid{2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was preparedfrom 2-(2-methoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acidand N-(2-methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine. LCMS calcd forC20H20F3N5O4 (m/e) 451. obsd 452 (M+H).

Example 75 Preparation of 2-phenyl-5-propyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,2-phenyl-5-propyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-phenyl-5-propyl-oxazole-4-carboxylic acid andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC22H26N4O3 (m/e) 394, obsd 395 (M+H).

Example 76 Preparation of 2-phenyl-5-propyl-oxazole-4-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide

With a procedure similar to example 16 above,2-phenyl-5-propyl-oxazole-4-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from2-phenyl-5-propyl-oxazole-4-carboxylic acid and6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C22H24N4O3 (m/e) 392,obsd 393 (M+H).

Example 77 Preparation of2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC22H25ClN4O3 (m/e) 428, obsd 429 (M+H).

Example 78 Preparation of2-(2-bromo-phenyl)-5-propyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,2-(2-bromo-phenyl)-5-propyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]pyridin-3-yl}-amide was prepared from2-(2-bromo-phenyl)-5-propyl-oxazole-4-carboxylic acid andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC22H25BrN4O3 (m/e) 473, obsd 474 (M+H).

Example 79 Preparation of 5-propyl-2-o-tolyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,5-propyl-2-o-tolyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-(2-bromo-phenyl)-5-propyl-oxazole-4-carboxylic acid andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC23H28N4O3 (m/e) 408, obsd 409 (M+H).

Example 80 Preparation of2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid[6-(ethyl-methyl-amino)-pyridin-3-yl]-amide

With a procedure similar to example 16 above,2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid[6-(ethyl-methyl-amino)-pyridin-3-yl]-amide was prepared from2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid andN²-ethyl-N²-methyl-pyridine-2,5-diamine. LCMS calcd for C21H23ClN4O2(m/e) 398, obsd 399 (M+H).

Example 81 Preparation of 2-cyclohexyl-5-propyl-oxazole-4-carboxylicacid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 16 above,2-cyclohexyl-5-propyl-oxazole-4-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-cyclohexyl-5-propyl-oxazole-4-carboxylic acid andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC22H32N4O3 (m/e) 400, obsd 401 (M+H).

Example 82 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(2-hydroxy-ethylamino)-pyridin-3-yl]-amide

A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (311mg, 1.21 mmol), 2-(5-amino-pyridin-2-ylamino)-ethanol (84 mg, 0.55mmol), N-hydroxybenzotriazole (185 mg, 1.38 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (264 mg,1.38 mmol) in a mixture of methylene chloride (5 mL) and DMF (1 mL) wasstirred at room temperature for 5 hr. The solvents were removed, andlithium hydroxide hydrate (excess) in a mixed solvent of methanol,tetrahydrofuran, and water (3:1:1, 5 mL) was added. The reaction mixturewas stirred at room temperature for overnight. Solvents were removed,and water was added. The resulted mixture was extracted twice with ethylacetate. The organic layers were collected, and washed with water,brine, dried over sodium sulfate, filtered, and concentrated in vacuo.Flash chromatography (Merck silica gel 60, 230-400 mesh, 0-15% methanolin methylene chloride for 30 min), and then preparative HPLC (0-90%acetonitrile in water for 20 min), followed by lyophilization gave2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(2-hydroxy-ethylamino)-pyridin-3-yl]-amide as a light yellow solid.LCMS calcd for C18H15F3N4O3 (m/e) 392, obsd 393 (M+H).

Example 83 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-hydroxy-ethyl)-methyl-amino-]-pyridin-3-yl}-amide

With a procedure similar to example 43 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and2-[(5-amino-pyridin-2-yl)-methyl-amino]-ethanol. LCMS calcd forC19H17F3N4O3 (m/e) 406, obsd 407 (M+H).

Example 84 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide

With a procedure similar to example 43 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and1-(5-amino-pyridin-2-yl)-pyrrolidin-3-ol. LCMS calcd for C20H17F3N4O3(m/e) 418, obsd 419 (M+H).

Example 85 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid-[2-(3-hydroxypyrrolidin-1-yl)-pyrimidin-5-yl]amide

With a method similar to example 43 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid-[2-(3-hydroxypyrrolidin-1-yl)pyrimidin-5-yl]amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN-(5-amino-pyrimidin-2-yl)-pyrrolidin-3-ol. LCMS calcd for C19H16F3N5O3m/e 419.37, obsd 420.0 (ES, M+H).

Example 86 Preparation of(R)-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid-[2-(3-hydroxypyrrolidin-1-yl)pyrimidin-5-yl]amide

With a method similar to example 43 above,(R)-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid-[2-(3-hydroxypyrrolidin-1-yl)pyrimidin-5-yl]amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and(R)—N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol. LCMS calcd forC19H16F3N5O3 m/e 419.37, obsd 420.1 (ES, M+H).

Example 87 Preparation of(S)-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid-[2-(3-hydroxypyrrolidin-1-yl)pyrimidin-5-yl]amide

With a method similar to example 43 above,(S)-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid-[2-(3-hydroxypyrrolidin-1-yl)pyrimidin-5-yl]amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and(S)—N-(5-aminopyrimidin-2-yl)-pyrrolidin-3-ol. LCMS calcd forC19H16F3N5O3 m/e 419.37, obsd 420.1 (ES, M+H).

Example 88 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(3-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide

With a procedure similar to example 43 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(3-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide wasprepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and5′-amino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3-ol. LCMS calcd forC21H19F3N4O3 (m/e) 432, obsd 433 (M+H).

Example 89 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(S)-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]amide

With a procedure similar to example 43 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-amide wasprepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and[(S)-1-(5-amino-pyridin-2-yl)-pyrrolidin-2-yl]-methanol. LCMS calcd forC21H19F3N4O3 (m/e) 432, obsd 433 (M+H).

Example 90 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide

With a procedure similar to example 43 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(4-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide wasprepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and5′-amino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol. LCMS calcd forC21H19F3N4O3 (m/e) 432, obsd 433 (M+H).

Example 91 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-((S)-2-hydroxy-1-methyl-ethylamino)-pyridin-3-yl]-amide

With a procedure similar to example 43 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-((S)-2-hydroxy-1-methyl-ethylamino)-pyridin-3-yl]amide was preparedfrom 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and(S)-2-(5-amino-pyridin-2-ylamino)-propan-1-ol. LCMS calcd forC19H17F3N4O3 (m/e) 406, obsd 407 (M+H).

Example 92 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[2-((S)-2-hydroxy-1-methyl-ethylamino)-pyrimidin-5-yl]-amide

With a procedure similar to example 43 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[2-((S)-2-hydroxy-1-methyl-ethylamino)-pyrimidin-5-yl]amide was preparedfrom 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and(S)-2-(5-amino-pyrimidin-2-ylamino)-propan-1-ol. LCMS calcd forC18H16F3N5O3 (m/e) 407, obsd 408 (M+H).

Example 93 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(2-hydroxy-1,1-dimethyl-ethylamino)-pyridin-3-yl]-amide

With a procedure similar to example 43 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(2-hydroxy-1,1-dimethyl-ethylamino)-pyridin-3-yl]-amide was preparedfrom 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and2-(5-Amino-pyridin-2-ylamino)-2-methyl-propan-1-ol. LCMS calcd forC20H19F3N4O3 (m/e) 420, obsd 421 (M+H).

Example 94 Preparation of2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid[6-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide

With a method similar to example 43 above,2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid[6-((S)-3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide was prepared from2-(2-bromo-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and(S)-1-(5-Amino-pyridin-2-yl)-pyrrolidin-3-ol. LCMS calcd forC20H16BrF3N4O3 m/e 497, obsd 498.

Example 95 Preparation of2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide

A mixture of 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester (174 mg, 0.5 mmol) and6-morpholin-4-yl-pyridin-3-ylamine (90 mg, 0.5 mmol) in 5 mL ofacetonitrile was stirred at 85° C. overnight. The solvent was removed invacuo, and the crude product was purified by flash chromatography (Mercksilica gel 60, 230-400 mesh, 0-15% methanol in methylene chloride for 30min) to yield 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide (107 mg, 52% yield) as a lightyellow solid. LCMS calcd for C21H21ClN4O3 (m/e) 412, obsd 413 (M+H).

Example 96 Preparation of2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide

With a procedure similar to example 50 above,2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester and 6-morpholin-4-yl-pyridin-3-ylamine.LCMS calcd for C22H23ClN4O3 (m/e) 426, obsd 427 (M+H).

Example 97 Preparation of 4-methyl-2-o-tolyl-oxazole-5-carboxylic acid(6-morpholin-4-yl-pyrdin-3-yl)amide

With a procedure similar to example 50 above,4-methyl-2-o-tolyl-oxazole-5-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from4-methyl-2-o-tolyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-ylester and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C21H22N4O3(m/e) 378, obsd 379 (M+H).

Example 98 Preparation of 4-propyl-2-o-tolyl-oxazole-5-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide

With a procedure similar to example 50 above,4-propyl-2-o-tolyl-oxazole-5-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from4-propyl-2-o-tolyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-ylester and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C23H26N4O3(m/e) 406, obsd 407 (M+H).

Example 99 Preparation of 4-methyl-2-phenyl-oxazole-5-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)

With a procedure similar to example 50 above,4-methyl-2-phenyl-oxazole-5-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from4-methyl-2-phenyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-ylester and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C20H20N4O3(m/e) 364, obsd 365 (M+H).

Example 100 Preparation of4-(2-methylsulfanyl-ethyl)-2-phenyl-oxazole-5-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide

With a procedure similar to example 50 above,4-(2-methylsulfanyl-ethyl)-2-phenyl-oxazole-5-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from4-(2-methylsulfanyl-ethyl)-2-phenyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester and 6-morpholin-4-yl-pyridin-3-ylamine.LCMS calcd for C22H24N4O3S (m/e) 424, obsd 425 (M+H).

Example 101 Preparation of2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 50 above,2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-(2-chloro-phenyl)-4-ethyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC21H23ClN4O3 (m/e) 414, obsd 415 (M+H).

Example 102 Preparation of2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 50 above,2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC22H25ClN4O3 (m/e) 428, obsd 429 (M+H).

Example 103 Preparation of 2-phenyl-4-propyl-oxazole-5-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 50 above,2-phenyl-4-propyl-Oxazole-5-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-phenyl-4-propyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC22H26N4O3 (m/e) 394, obsd 395 (M+H).

Example 104 Preparation of 2-cyclohexyl-4-propyl-oxazole-5-carboxylicacid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 50 above,2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC22H32N4O3 (m/e) 400, obsd 401 (M+H).

Example 105 Preparation of 2-cyclohexyl-4-propyl-oxazole-5-carboxylicacid (6-morpholin-4-yl-pyridin-3-yl)-amide

With a procedure similar to example 50 above,2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester and 6-morpholin-4-yl-pyridin-3-ylamine.LCMS calcd for C22H30N4O3 (m/e) 398, obsd 399 (M+H).

Example 106 Preparation of 2-phenyl-4-propyl-oxazole-5-carboxylic acid[6-(ethyl-methyl-amino)-pyridin-3-yl]-amide

With a procedure similar to example 50 above,2-phenyl-4-propyl-oxazole-5-carboxylic acid[6-(ethyl-methyl-amino)-pyridin-3-yl]amide was prepared from2-phenyl-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-ylester and N²-ethyl-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC21H24N4O2 (m/e) 364, obsd 365 (M+H).

Example 107 Preparation of2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]pyridin-3-yl}-amide

With a procedure similar to example 50 above,2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC22H25BrN4O3 (m/e) 473, obsd 474 (M+H).

Example 108 Preparation of2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid{2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide

With a procedure similar to example 50 above,2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid{2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was preparedfrom 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester andN-(2-methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine. LCMS calcd forC21H24BrN5O3 (m/e) 474, obsd 475 (M+H).

Example 109 Preparation of2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid[6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide

With a procedure similar to example 50 above,2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid[6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide was prepared from2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester andN²-cyclopropyl-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC22H23BrN4O2 (m/e) 455, obsd 456 (M+H).

Example 110 Preparation of2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid[6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide

With a procedure similar to example 50 above,2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid[6-(cyclopropyl-methyl-amino)-pyridin-3-yl]-amide was prepared from2-(2-chloro-phenyl)-4-propyl-oxazole-5-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester andN²-cyclopropyl-N²-methyl-pyridine-2,5-diamine LCMS calcd forC22H23ClN4O2 (m/e) 410, obsd 411 (M+H).

Example 111 Preparation of2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 1 above,2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid andN²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC20H19F3N4O3 (m/e) 420, obsd 421 (M+H).

Example 112 Preparation of2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid{2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide

With a procedure similar to example 1 above,2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid{2[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was preparedfrom 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid andN-(2-Methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine. LCMS calcd forC19H18F3N5O3 (m/e) 421, obsd 422 (M+H).

Example 113 Preparation of2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

With a procedure similar to example 1 above,2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid{6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was preparedfrom 2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acidand N²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcd forC21H21F3N4O4 (m/e) 450, obsd 451 (M+H).

Example 114 Preparation of2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid{2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide

With a procedure similar to example 1 above,2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid{2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was preparedfrom 2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acidand N-(2-methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine. LCMS calcd forC20H20F3N5O4 (m/e) 451, obsd 452 (M+H).

Example 115 Preparation of2-[2-(2-methoxy-ethoxy)-phenyl]-4-trifluoromethyl-oxazole-5-carboxylicacid {6-[(2-methoxy-ethyl)-methyl-amino]pyridin-3-yl}-amide

With a procedure similar to example 1 above,2-[2-(2-methoxy-ethoxy)-phenyl]-4-trifluoromethyl-oxazole-5-carboxylicacid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide wasprepared from2-[2-(2-methoxy-ethoxy)-phenyl]-4-trifluoromethyl-oxazole-5-carboxylicacid and N²-(2-methoxy-ethyl)-N²-methyl-pyridine-2,5-diamine. LCMS calcdfor C23H25F3N4O5 (m/e) 494, obsd 495 (M+H).

Example 116 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(1-oxo-1λ⁴-thiomorpholin-4-yl)-pyridin-3-yl]-amide

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-thiomorpholin-4-yl-pyridin-3-yl)-amide (30 mg, 0.07 mmol) wasdissolved in 3 mL of methylene chloride, and cooled down to −78° C. Oneequivalent of 3-chloroperoxybenzoic acid (12 mg, 0.07 mmol) was added.The reaction mixture was warmed up to room temperature and stirred for 2hours. The reaction mixture was concentrated under reduced pressure, andthen purified by flash chromatography (Merck silica gel 60, 230-400mesh, 0-20% methanol in methylene chloride for 25 min) to gave2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(1-oxo-1λ⁴-thiomorpholin-4-yl)-pyridin-3-yl]-amide as an off-whitesolid. LCMS calcd for C20H17F3N4O3S (m/e) 450, obsd 451 (M+H).

Example 117 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-pyridin-3-yl]-amide

With a procedure similar to example 58 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-pyridin-3-yl]amide was preparedfrom 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-thiomorpholin-4-yl-pyridin-3-yl)-amide and two equivalents of3-chloroperoxybenzoic acid. LCMS calcd for C20H17F3N4O4S (m/e) 466, obsd467 (M+H).

Example 118 Preparation of 5-cyclohexyl-2-methyl-furan-3-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide

5-Cyclohexyl-2-methyl-furan-3-carboxylic acid (83 mg, 0.365 mmol),6-morpholin-4-yl-pyridin-3-ylamine (83 mg, 0.4 mmol), and triethylamine(154 uL, 1.09 mmol) were dissolved in 5 mL of DMF and chilled in an icebath. To this solution was added BOP (169 mg, 0.383 mmol) in oneportion. The mixture was stirred at room temperature for one hour andthen diluted with 30 mL ethyl acetate. The ethyl acetate solution waswashed with saturated sodium bicarbonate (2×10 mL) and saturated sodiumchloride (10 mL). The organic layer was dried over MgSO₄, filtered andevaporated to dryness under vacuum. The crude product was purified byflash chromatography using ethyl acetate/hexane to yield5-cyclohexyl-2-methyl-furan-3-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide as a light grey powder (87 mg,64%). ES-MS calcd for C21H27N3O3 (m/e) 369.5, obsd 370.3 (M+H).

Example 119 Preparation of 5-cyclohexyl-2-ethyl-furan-3-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide

5-Cyclohexyl-2-ethyl-furan-3-carboxylic acid (26 mg, 0.116 mmol),6-morpholin-4-yl-pyridin-3-ylamine (20 mg, 0.116 mmol), andtriethylamine (49 uL, 0.348 mmol) were dissolved in 4 mL of DMF andchilled in an ice bath. To this solution was added BOP (53 mg, 0.121mmol) in one portion. The mixture was stirred at room temperature forone hour and then diluted with 30 mL ethyl acetate. The ethyl acetatesolution was washed with saturated sodium bicarbonate (2×10 mL) andsaturated sodium chloride (10 mL) The organic layer was dried overMgSO₄, filtered and evaporated to dryness under vacuum. The crudeproduct was purified by flash chromatography using ethyl acetate/hexaneto yield 5-cyclohexyl-2-ethyl-furan-3-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide as a light grey powder (11.5 mg,26%). ES-MS calcd for C22H29N3O3 (m/e) 383.5, obsd 384 (M+H).

Example 120 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[5-(N-2-methoxyethyl-N-methyl)aminopyrazine]-2-yl-amide

To a suspension of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(285 mg, 1.1 mmol) in methylene chloride (10 mL) cooled with an ice bathwas added oxalyl chloride (0.22 mL, 2.5 mmol) and one drop of DMF. Themixture was stirred at 0° C. for 5 minutes and then at room temperaturefor 30 minutes. Solvents were evaporated and the residue was treatedwith toluene (10 mL) and solvents were further evaporated. The residuewas dried in vacuum and dissolved in methylene chloride (10 mL). Thesolution was cooled in an ice bath and treated with a methylene chloridesolution (10 mL) containing pyridine (0.24 mL, 2.97 mmol) and5-(N²-methoxyethyl-N-methyl)-pyrazine-2,5-diamine (180 mg, 1.0 mmol).Ice bath was removed and the mixture was stirred at room temperature for90 minutes. The mixture was then extracted with methylene chloride andwater. The organic layer was washed with aqueous sodium bicarbonatesolution and brine, dried over sodium sulfate and concentrated. Theresidue was purified through a Biotage flash column chromatographyeluted with ethyl acetate and hexanes (gradient elution with 10% to 50%ethyl acetate in hexanes) to give2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[5-(N-2-methoxyethyl-N-methyl)aminopyrazine]-2-yl-amide as a yellowsolid (205 mg, 48%). LCMS calcd for C19H18F3N5O3 (m/e) 421.3, obsd 422.2(M+H).

Example 121 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[5-(N-tetrahyropyran-4-yl)aminopyrazine]-2-yl-amide

With a procedure similar to example 62 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[5-(N-tetrahyropyran-4-yl)aminopyrazine]-2-yl-amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid andN-(tetrahydropyran-4-yl)pyrazine-2,5-diamine. LCMS calcd forC20H18F3N5O3 (m/e) 433, obsd 434 (M+H).

Example 122 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid-[6-(tetrahydropyran-4-yl-amino)pyridine-3-yl]amide

To a N,N-dimethylformamide solution (5 mL) containing2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (134 mg, 0.52 mmol)and 2-(N-tetrahydropyran-4-yl)-2,5-diaminopyridine (101 mg, 0.52 mmol)was added triethylamine (0.15 mL, 1.0 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (243 mg, 0.52 mmol). Themixture was stirred at room temperature overnight. Solvents wereevaporated and the residue was purified through flash columnchromatography using ethyl acetate and hexanes (1/1 to 2/1 ratio) togive a fluffy solid (108 mg). LCMS calcd for C21H19F3N4O3 m/e 432.41,obsd 433.1 (ES, M+H).

Example 123 Preparation of(S)-2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid-[6-(tetrahydrofuran-3-ylamino)pyridin-3-yl]amide

With a method similar to example 17 above,(S)-2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid-[6-(tetrahydrofuran-3-ylamino)pyridin-3-yl]amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and(S)-2-N-(tetrahydrofuran-3-yl)-2,5-diaminopyridine. LCMS calcd forC20H17F3N4O3 m/e 418.38, obsd 419.2 (AP, M+H).

Example 124 Preparation of2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid-[6-(tetrahydrofuran-3-ylamino)pyridin-3-yl]amide

With a method similar to example 17 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid-[6-(tetrahydrofuran-3-ylamino)pyridin-3-yl]amide was prepared from2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and2-N-(tetrahydrofuran-3-yl)-2,5-diaminopyridine. LCMS calcd forC20H17F3N4O3 m/e 418.38, obsd 419.13 (ES, M+H).

Example 125 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(cis-3-hydroxy-cyclopentylamino)-pyridin-3-yl]amide

A mixture of 5-methyl-2-phenyl-oxazole-4-carboxylic acid (371 mg, 1.44mmol), DCM (5 mL), and DMF (cat.) was stirred under Ar, cooled in an icebath, and oxalyl chloride (252 μL, 2.89 mmol) was added dropwise intothe mixture over 5 min. The mixture was immediately allowed to warm toroom temperature and after 1.5 hr the reaction was concentrated todryness and then dried again from DCM. The white yellow solid wasdissolved in 5 mL of DCM and added dropwise into a solution containingN²-[cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamine(443.7 mg, 1.44 mmol), DMAP (cat.), and TEA (602 μL, 4.33 mmol) in 5 mLof DCM under Ar cooled in an ice bath. The reaction was allowed to warmto room temperature overnight. The reaction was concentrated, supportedonto silica gel, and purified by flash chromatography using the Analogixsystem with a 40 g Redisep silica gel column with increasingconcentrations of EtOAc in hexane (30 mL/min, equilibrate with 5%, 0-5min: 5%, 5-20 min: 5 to 30%, 20-40 min: 30%). The appropriate fractionswere collected and dried producing a red solid,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-pyridin-3-yl}-amide,456 mg, 72.9% (LCMS 3.91 min, 547 (M+H), calcd. C27H33F3N4O3S (m/e) 546,10-100% ACN in H₂O/HCOOH 0.3%, C18, ESI). The protected alcohol wasdissolved in ACN (10 mL) and 5% aqueous HF solution (1.3 mL) was addedslowly dropwise. The reaction was stirred for 22 hr, concentrated, andliquid extracted with DCM. The organic layer was washed with saturatedsodium bicarbonate and brine, dried over sodium sulfate, andconcentrated to dryness. The dried material was redissolved in DCM (14mL) and TFA (6 mL) was added slowly dropwise. After 1.5 hr the solutionwas concentrated to dryness, supported on silica gel, and purified byflash chromatography with a 12 g 12M Biotage silica gel column withincreasing concentrations of EtOAc in Hexane (250 mL increments of 5,10, 30, 50, 80, 100% and then 5% MeOH in EtOAc). The appropriatefractions were collected and dried producing a white/yellow solid 189mg, 53% (LCMS 3.00 min, 433 (M+H), calcd. C21H19F3N4O3 (m/e) 432,10-100% ACN in H₂O/HCOOH 0.3%, C18, APCI).

Example 126 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(trans-3-hydroxy-cyclopentylamino)-pyridin-3-yl]-amide

With a procedure similar to example 64 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(trans-3-hydroxy-cyclopentylamino)-pyridin-3-yl]amide was preparedfrom 2-phenyl-oxazole-4-carboxylic acid andN²-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-pyridine-2,5-diamine.The product was light yellow, 880 mg, 89% yield, (LCMS 2.71 min, 433(M+H), calcd. C21H19F3N4O3 (m/e) 432, 10-100% ACN in H₂O/HCOOH 0.3%,C18, APCI).

Example 127 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-((1S,3S)-[3-hydroxy-cyclopentylamino]-pyridin-3-yl}-amide

To a flask containing 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid{6-((1S,3S)-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-pyridin-3-yl}-amide(8 mg, 0.015 mmol) was added dichloromethane (0.7 mL) andtrifluoroacetic acid (0.3 mL). When the starting material was consumed,as indicated by TLC, the reaction mixture was neutralized withtriethylamine and concentrated to dryness. The residue was dissolved ina minimal amount of dichloromethane and hexanes were added dropwise toprecipitate the product. The light pink solid was filtered and washedwith hexanes to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid {6-((1S,3S)-[3-hydroxy-cyclopentylamino]-pyridin-3-yl}-amide. LCMSfor C₂₁H₁₉F₃N₄O₃ calculated (m/e) 432, found 433 (M+H).

Example 128 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-((1R,3R)-[3-hydroxy-cyclopentylamino]-pyridin-3-yl}-amide

With a method similar to that used for the preparation2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6)(1S,3S)-[3-hydroxy-cyclopentyl amino]-pyridin-3-yl}-amide above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-((1R,3R)-[3-hydroxy-cyclopentylamino]-pyridin-3-yl}-amide wasprepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6((1R,3R)-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamino]-pyridin-3-yl}-amide.LCMS for C₂₁H₁₉F₃N₄O₃ calculated (m/e) 432, found 433 (M+H).

Example 129 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[5-(3-(S)-methoxy-pyrrolidinyl)-pyridin-2-yl]-amide

A solution of (170 mg, 0.76 mmol) of5-(3-(S)-methoxy-pyrrolidin-1-yl)-2-nitro-pyridine in EtOH (20 mL) wastreated with 10% Pd/C (80 mg, 0.08 mmol). The resulting mixture washydrogenated under atmospheric pressure for 1 h and then filtered. Thesolids were washed three times with EtOH and the combined organic layerwas evaporated to the corresponding crude aminopyridine. This product,without further characterization, was dissolved in CH₂Cl₂ (15 mL). Theresulting solution was then treated with diisopropylethylamine (790 μL,4.6 mmol) and a catalytic amount of DMAP.

A slurry of 220 mg (0.83 mmol) of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid in CH₂Cl₂ (15 mL)was treated with 80 μL (0.92 mmol) of oxalyl chloride and a catalyticamount of DMF at rt. After stirring for 10 min the slurry disappeared.The solvent was evaporated under reduced pressure to dryness to affordthe corresponding acid chloride. This intermediate, withoutcharacterization was dissolved in about 15 mL of CH₂Cl₂ and added undervigorous stirring to the solution that contained the crude aminopyridineproduct described above. This combined mixture was stirred for 30 minand then concentrated. The residue was chromatographed on a silica gelcolumn with a 0-20% Et₂O in toluene gradient to afford the product as ayellow solid. (170 mg, 52% yield). HRMS m/z calcd for C₂₁H₁₉F₃N₄O₃[M+H]⁺: 433.1482; Found: 433.1482.

Example 130 Preparation of2-phenyl-5-trifluormethyl-oxazole-4-carboxylicacid{5-[(2-methoxy-ethyl)-methyl-amino]-pyridin-2-yl}amide

With a procedure similar to example 66 above,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{5-[(2-methoxy-ethyl)-methyl-amino]-pyridin-2-yl}amide was prepared from(2-methoxyethyl)-methyl-(6-nitropyridin-3-yl)-amine and2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid. The product wasisolated as a yellow solid (200 mg, 37% yield). HRMS m/z calcd forC₂₀H₁₉F₃N₄O₃ [M+H]⁺: 421.1482; Found: 421.1481.

Example 131 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(3-hydroxyazetidin-1-yl)-pyridin-3-yl]-amide

1-(5-Nitro-pyridin-2-yl)-azetidin-3-ol (400 mg, 2 mmol) was hydrogenatedat 35 psi for 2¾ hrs with 10% Pd/C (40 mg) in EtOH (30 mL) and aceticacid (2 drops). The mixture was filtered through a celite plug,evaporated and then co-evaporated with toluene. The residue wasdissolved in DMF (15 mL). One half of this solution (7.5 mL, ˜1 mmol)was removed. To this was added2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (257 mg, 1 mmol),Et₃N (422 uL, 3 mmol) and BOP (464 mg. 1.05 mmol). The reaction wasstirred for 1 hr at room temperature. Following work-up as above, thecrude material was purified by flash chromatography to yield2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(3-hydroxyazetidin-1-yl)-pyridin-3-yl]amide as an off-white solid (41mg). ES-MS calcd for C19H15F3N4O3 (m/e) 404.35, obsd 405.1 (M+H).

Example 132 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-ethoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

(2-Ethoxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (150 mg, 0.666mmol) was hydrogenated as above and reacted with2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (171 mg, 0.666mmol), Et₃N (464 uL, 3.3 mmol) and BOP (309 mg. 0.699 mmol). Followingwork-up as above, the crude material was purified by flashchromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid {6-[(2-ethoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide as a yellowsolid (194 mg). ES-MS calcd for C21H21F3N4O3 (m/e) 434.42, obsd 435.1(M+H).

Example 133 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(3-methoxy-azetidin-1-yl)-pyridin-3-yl]-amide

2-(3-Methoxy-azetidin-1-yl)-5-nitro-pyridine (120 mg, 0.5 mmol) washydrogenated as above and reacted with2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (141 mg, 0.55mmol), Et₃N (352 uL, 2.5 mmol) and BOP (232 mg. 0.525 mmol). Followingwork-up as above, the crude material was purified by flashchromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid [6-(3-methoxy-azetidin-1-yl)-pyridin-3-yl]-amide as a light greensolid (45 mg). ES-MS calcd for C20H17F3N4O3 (m/e) 418.38, obsd 419.1(M+H).

Example 134 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(6-sec-butylamino-pyridin-3-yl)-amide

sec-Butyl-(5-nitro-pyridin-2-yl)-amine (97.5 mg, 0.5 mmol) washydrogenated as above and reacted with2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (135 mg, 0.525mmol), Et₃N (352 uL, 2.5 mmol) and BOP (232 mg. 0.525 mmol). Followingwork-up as above, the crude material was purified by flashchromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid (6-sec-butylamino-pyridin-3-yl)-amide as a light purple solid (83mg). ES-MS calcd for C20H19F3N4O2 (m/e) 404.40, obsd 405.1 (M+H).

Example 135 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(3-ethoxy-azetidin-1-yl)-pyridin-3-yl]-amide

2-(3-Ethoxy-azetidin-1-yl)-5-nitro-pyridine (59 mg, 0.264 mmol) washydrogenated as above and reacted with2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (74 mg, 0.29 mmol),Et₃N (186 uL, 1.32 mmol) and BOP (122 mg. 0.277 mmol). Following work-upas above, the crude material was purified by flash chromatography toyield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(3-ethoxy-azetidin-1-yl)-pyridin-3-yl]-amide as a solid (79 mg).ES-MS calcd for C21H19F3N4O3 (m/e) 432.41, obsd 433.1 (M+H).

Example 136 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-cyclopropylmethoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide

(2-Cyclopropylmethoxy-ethyl)-methyl-(5-nitro-pyridin-2-yl)-amine (82 mg,0.326 mmol) was hydrogenated as above and reacted with2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (92 mg, 0.359mmol), Et₃N (229 uL, 1.63 mmol) and BOP (151 mg. 0.326 mmol). Followingwork-up as above, the crude material was purified by flashchromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid {6-[(2-cyclopropylmethoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amideas a solid (95 mg). ES-MS calcd for C23H23F3N4O3 (m/e) 460.46, obsd461.1 (M+H).

Example 137 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{2-[(2-ethoxy-ethyl)-methyl-amino]pyrimidin-5-yl}-amide

(2-Ethoxy-ethyl)-methyl-(5-nitro-pyrimidin-2-yl)-amine (150 mg, 0.663mmol) was hydrogenated as above and reacted with2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (179 mg, 0.696mmol), Et₃N (466 uL, 3.3 mmol) and BOP (308 mg. 0.696 mmol). Followingwork-up as above, the crude material was purified by flashchromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid {2-[(2-ethoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide as ayellow solid (6 mg). ES-MS calcd for C20H20F3N5O3 (m/e) 435.41, obsd436.1 (M+H).

Example 138 Preparation of(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino-]-pyridin-2-yl}-azetidin-3-yloxy)-aceticacid tert-butyl ester

[1-(5-Nitro-pyridin-2-yl)-azetidin-3-yloxy]-acetic acid tert-butyl ester(210 mg, 0.679 mmol) was hydrogenated as above and reacted with2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (183 mg, 0.71mmol), DIPEA (355 uL, 2.03 mmol) and BOP (315 mg. 0.74 mmol). Followingwork-up as above, the crude material was purified by flashchromatography to yield(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-azetidin-3-yloxy)-aceticacid tert-butyl ester as a light brown solid (169 mg). ES-MS calcd forC25H25F3N4O5 (m/e) 518.50, obsd 519.1 (M+H).

Example 139 Preparation of(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-azetidin-3-yloxy)-aceticacid hydrochloride

(1-{5-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-azetidin-3-yloxy)-aceticacid tert-butyl ester (132 mg) was treated with 8 mL of 97% TFA/H₂O for1 hr at room temperature. The reaction mixture was evaporated from 1NHCl (2×0.5 mL) to yield(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-azetidin-3-yloxy)-aceticacid hydrochloride as a off-white solid (130 mg). ES-MS calcd for freebase C21H17F3N4O5 (m/e) 462.39, obsd 463.0 (M+H).

Example 140 Preparation of(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-pyrrolidin-3-yloxy)-aceticacid tert-butyl ester

[1-(5-Nitro-pyridin-2-yl)-pyrrolidin-3-yloxy]-acetic acid tert-butylester (280 mg, 0.866 mmol) was hydrogenated as above and reacted with2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (245 mg, 0.953mmol), Et₃N (486 uL, 3.46 mmol) and BOP (402 mg. 0.909 mmol). Followingwork-up as above, the crude material was purified by flashchromatography to yield(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-pyrrolidin-3-yloxy)-aceticacid tert-butyl ester as a solid (170 mg). ES-MS calcd for C26H27F3N4O5(m/e) 532.52, obsd 533.1 (M+H).

Example 141 Preparation of(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-pyrrolidin-3-yloxy)-aceticacid hydrochloride

(1-{5-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-pyrrolidin-3-yloxy)-aceticacid tert-butyl ester (140 mg) was treated with 5 mL of 97% TFA/H₂O for1.5 hr at room temperature. The reaction mixture was evaporated from 1NHCl (2×0.5 mL) to yield(1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-azetidin-3-yloxy)-aceticacid hydrochloride as an off-white solid (110 mg). ES-MS calcd for freebase C22H21F3N4O5 (m/e) 476.42, obsd 477.1 (M+H).

Example 142 Preparation of[2-(methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-ethoxy]-aceticacid tert-butyl ester

{2-[Methyl-(5-nitro-pyridin-2-yl)-amino]-ethoxy}-acetic acid tert-butylester (218 mg, 0.7 mmol) was hydrogenated as above and reacted with2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (189 mg, 0.735mmol), Et₃N (394 uL, 2.8 mmol) and BOP (325 mg. 0.735 mmol). Followingwork-up as above, the crude material was purified by flashchromatography to yield[2-(methyl-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-amino)-ethoxy]-aceticacid tert-butyl ester as a solid (110 mg). ES-MS calcd for C25H27F3N4O5(m/e) 520.51, obsd 521.1 (M+H).

Example 143 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[methyl-(3-methyl-butyl)-amino]pyridin-3-yl}-amide

Methyl-(3-methyl-butyl)-(5-nitro-pyridin-2-yl)-amine (110 mg, 0.49 mmol)was hydrogenated as above and reacted with2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (138 mg, 0.54mmol), Et₃N (352 uL, 2.5 mmol) and BOP (227 mg. 0.514 mmol). Followingwork-up as above, the crude material was purified by flashchromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid {6-[methyl-(3-methyl-butyl)-amino]-pyridin-3-yl}-amide as a lightpurple solid (16 mg). ES-MS calcd for C22H23F3N4O2 (m/e) 432.51, obsd433.2 (M+H).

Example 144 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{6-[(2-cyano-ethyl)-methyl-amino]-pyridin-3-yl}-amide

3-[Methyl-(5-nitro-pyridin-2-yl)-amino]-propionitrile (103 mg, 0.5 mmol)was hydrogenated as above and reacted with2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (108 mg, 0.423mmol), Et₃N (297 uL, 2.11 mmol) and BOP (196 mg. 0.444 mmol). Followingwork-up as above, the crude material was purified by flashchromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid {6-[(2-cyano-ethyl)-methyl-amino]-pyridin-3-yl}-amide as a solid(61 mg). ES-MS calcd for C20H16F3N5O2 (m/e) 415.38, obsd 416.1 (M+H).

Example 145 Preparation of2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid[6-(bicyclo[2.2.1]hept-2-ylamino)-pyridin-3-yl]-amide

Bicyclo[2.2.1]hept-2-yl-(5-nitro-pyridin-2-yl)-amine (102 mg, 0.4 mmol)was hydrogenated as above and reacted with2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (123 mg, 0.48mmol), Et₃N (281 uL, 2 mmol) and BOP (194 mg. 0.444 mmol). Followingwork-up as above, the crude material was purified by flashchromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylicacid [6-(bicyclo[2.2.1]hept-2-ylamino)-pyridin-3-yl]-amide as a lightpurple solid (30 mg). ES-MS calcd for C23H21F3N4O2 (m/e) 442.44, obsd443.2 (M+H).

Example 146 DGAT Phospholipid FlashPlate Assay

Materials for the assay were: PL-FlashPlate: Phospholipid FlashPlatesfrom PerkinElmer, catalog number SMP108; DAG (1,2-Dioleoyl-sn-glycerol)10 mM suspended in water containing 0.1% Triton X-100; ¹⁴C-Pal-CoA(palmitoyl coenzyme A, [palmitoyl-1-¹⁴C]) from PerkinElmer, catalognumber NEC-555 with a specific activity of 55 mCi/mmol; and DGAT pellet,with a protein concentration of 9.85 mg/mL.

Aqueous buffers were prepared or purchased as follows: The coatingbuffer (CB) was purchased from PerkinElmer, catalog number SMP900A; thereaction buffer (RB) was 50 mM Tris-HCl, pH 7.5, 100 mM NaCl, 0.01% BSAin water; the washing buffer (WB) is 50 mM Tris-HCl, pH 7.5, 100 mMNaCl, 0.05% deoxycholic acid sodium salt in water; the dilution buffer(DB) was 50 mM Tris-HCl, pH 7.5, 100 mM NaCl, 1 mM EDTA, 0.2% TritonX-100 in water.

1,2-Dioleoyl-sn-glycerol (DAG, 10 mmoles) was diluted to 500 μM withcoating buffer (CB). The diluted DAG solution was then added to 384-wellPL-FlashPlates at 60 μl per well, and incubated at room temperature for2 days. The coated plates were then washed twice with washing buffer(WB) before use. Test compounds were serial diluted to 2000, 666.7,222.2, 74.1, 24.7, 8.2, 2.7 and 0.9 μM in 100% DMSO. Diluted compoundwere further diluted 10 fold with reaction buffer (RB). ¹⁴C-Pal-CoA wasdiluted to 8.3 μM with RB. The DGAT pellet was diluted to 0.13 mgprotein/mL with dilution buffer (DB) immediately before it was added tothe PL-FlashPlates to start the reaction. 20 μl of the RB-dilutedcompounds (or 10% DMSO in RB for Total and Blank), 15 μRB diluted14C-Pal-CoA and 15 μl of DB diluted DGAT pellet (DB without DGAT forBlanks) were transferred to each well of the PL-FlashPlates. Thereaction mixtures were incubated at 37° C. for 1 hour. The reactionswere stopped by washing 3 times with WB. Plates were sealed withTop-seal and read on a Topcount instrument.

Calculation of IC₅₀: The IC₅₀ values for each compound were generatedusing an Excel template. The Topcount rpm readings of Total and Blankwere used as 0% and 100% inhibition. The percent inhibition values ofreactions in the presence of compounds were calculated, and plottedagainst compound concentrations. All data were fitted into a DoseResponse One Site model (4 parameter logistic model) as the following:

(A+((B−A)/(1+((x/C)̂D)))),

with A and B as the bottom and top of the curve (highest and lowestinhibition), respectively, and C as IC₅₀ and D as Hill Coefficient ofthe compound. The results are summarized in Table 1 below:

TABLE 1 Activity in DGAT Phospholipid FlashPlate Assay Compound ofExample (A = IC₅₀ < 0.75 μM, B = IC₅₀ > 0.75 μM) 1 A 2 B 3 A 4 A 5 A 6 A7 A 8 A 9 A 10 A 11 A 12 B 13 A 14 A 15 A 16 A 17 A 18 B 18 A 20 B 21 B22 A 23 A 24 A 25 A 26 A 27 B 28 A 29 A 30 A 31 B 32 A 33 A 34 A 35 A 36A 37 B 38 A 39 A 40 A 41 A 42 A 43 A 44 A 45 A 46 A 47 A 48 A 49 A 50 B51 A 52 A 53 A 54 A 55 A 56 A 57 A 58 A 59 A 60 A 61 A 62 A 63 A 64 A 65A 66 A 67 A 68 A 69 A 70 A 71 A 72 A 73 A 74 A 75 A 76 A 77 A 78 A 79 A80 A 81 A 82 A 83 A 84 A 85 A 86 A 87 A 88 B 89 B 90 A 91 A 92 A 93 A 94A 95 A 96 A 97 A 98 A 99 A 100 A 101 A 102 A 103 A 104 A 105 B 106 A 107A 108 A 109 A 110 A 111 A 112 A 113 A 114 A 115 A 116 A 117 A 118 A 119A 120 B 121 A 122 A 123 A 124 A 125 A 126 A 127 A 128 A 129 B 130 B 131A 132 A 133 A 134 A 135 A 136 A 137 A 138 A 139 A 140 A 141 A 142 A 143A 144 A 145 A

It is to be understood that the invention is not limited to theparticular embodiments of the invention described above, as variationsof the particular embodiments may be made and still fall within thescope of the appended claims.

1. A compound of the formula (I):

wherein: R₁ is unsubstituted aryl, aryl substituted with a groupselected from the group consisting of alkyl, —O-alkyl, haloalkoxy,methoxy-ethoxy and halogen, heteroaryl, alkyl or cycloalkyl; R₂ is C orN; R₃ is C, N, S or O; R₄ is C, O, S or N; R₅ is C, N or S; R₆ is H,alkyl, halogen, haloalkyl, thioalkyl or hydrogen; R₇ is

at least one of R₈ or R₉ is N; and the other is carbon; R₁₀ is —NR₁₁R₁₂,O-alkyl, hydroxy-dimethylethylamino, hydroxyl-methylethylamino,cyclohept-2-ylamino, morpholino, thiomorpholino, oxothiomorpholino,dioxothiomorpholino, alkyl-carbamoyl-alkyl-amino, difluoroazetidine,ethoxyazetidine, azetidin-3-yloxy acetic acid tert-butyl ether,azetidine-3-yloxy acetic acid hydrochloride, or a 4- to 6-memberedcyclic ring having from 1 to 3 hetero ring atoms selected from the groupconsisting of S, N and O, unsubstituted or substituted with a groupselected from the group consisting of amino, amide, —N(CH₃)C(O)CH₃,cyclopropanecarbonyl-methyl, —OCH₃, —OCH₂C(O)OC(CH₃)₃, OCH₂C(O)OH,—CH₂OH, —CH₂OCH₃ and —OH; R₁₁ is H, lower alkyl, alkyl ether,alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl,ethoxymethyl, —CH₂CH₂CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to6-membered cyclic ring having from 1 to 3 hetero ring atoms selectedfrom the group consisting of S, N and O, unsubstituted or substitutedwith a group selected from the group consisting of —OCH₃, —CH₂OH,—CH₂OCH₃, —OCH₂C(O)OC(CH₃)₃, —OCH₂C(O)OH and —OH; R₁₂ is H or loweralkyl; or a pharmaceutically acceptable salt thereof.
 2. The compoundaccording to claim 1, wherein: R₁ is unsubstituted aryl or arylsubstituted with a group selected from the group consisting of alkyl andhalogen; R₂ is C; R₃ is N; R₄ is O; R₅ is C; R₆ is alkyl; R₇ is

at least one of R₈ or R₉ is N; and the other is carbon; R₁₀ is —NR₁₁R₁₂,O-alkyl, hydroxy-dimethylethylamino, hydroxyl-methylethylamino,cyclohept-2-ylamino, morpholino, thiomorpholino, oxothiomorpholino,dioxothiomorpholino, alkyl-carbamoyl-alkyl-amino, difluoroazetidine,ethoxyazetidine, azetidin-3-yloxy acetic acid tert-butyl ether,azetidine-3-yloxy acetic acid hydrochloride, or a 4- to 6-memberedcyclic ring having from 1 to 3 hetero ring atoms selected from the groupconsisting of S, N and O, unsubstituted or substituted with a groupselected from the group consisting of amino, amide, —N(CH₃)C(O)CH₃,cyclopropanecarbonyl-methyl, —OCH₃, —OCH₂C(O)OC(CH₃)₃, OCH₂C(O)OH,—CH₂OH, —CH₂OCH₃ and —OH; R₁₁ is H, lower alkyl, alkyl ether,alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl,ethoxymethyl, —CH₂CH₂CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to6-membered cyclic ring having from 1 to 3 hetero ring atoms selectedfrom the group consisting of S, N and O, unsubstituted or substitutedwith a group selected from the group consisting of —OCH₃, —CH₂OH,—CH₂OCH₃, —OCH₂C(O)OC(CH₃)₃, —OCH₂C(O)OH and —OH; R₁₂ is H or loweralkyl; or a pharmaceutically acceptable salt thereof.
 3. The compoundaccording to claim 1, wherein: R₁ is unsubstituted aryl or arylsubstituted with a group selected from the group consisting of alkyl andhalogen; R₂ is C; R₃ is O; R₄ is N; R₅ is C; R₆ is H, alkyl, halogen,haloalkyl, thioalkyl or hydrogen; R₇ is

at least one of R₈ or R₉ is N; and the other is carbon; R₁₀ is —NR₁₁R₁₂,O-alkyl, hydroxy-dimethylethylamino, hydroxyl-methylethylamino,cyclohept-2-ylamino, morpholino, thiomorpholino, oxothiomorpholino,dioxothiomorpholino, alkyl-carbamoyl-alkyl-amino, difluoroazetidine,ethoxyazetidine, azetidin-3-yloxy acetic acid tert-butyl ether,azetidine-3-yloxy acetic acid hydrochloride, or a 4- to 6-memberedcyclic ring having from 1 to 3 hetero ring atoms selected from the groupconsisting of S, N and O, unsubstituted or substituted with a groupselected from the group consisting of amino, amide, —N(CH₃)C(O)CH₃,cyclopropanecarbonyl-methyl, —OCH₃, —OCH₂C(O)OC(CH₃)₃, OCH₂C(O)OH,—CH₂OH, —CH₂OCH₃ and —OH; R₁₁ is H, lower alkyl, alkyl ether,alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl,ethoxymethyl, —CH₂CH₂CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to6-membered cyclic ring having from 1 to 3 hetero ring atoms selectedfrom the group consisting of S, N and O, unsubstituted or substitutedwith a group selected from the group consisting of —OCH₃, —CH₂OH,—CH₂OCH₃, —OCH₂C(O)OC(CH₃)₃, —OCH₂C(O)OH and —OH; R₁₂ is H or loweralkyl; or a pharmaceutically acceptable salt thereof.
 4. The compoundaccording to claim 1, wherein: R₁ is unsubstituted aryl, arylsubstituted with a group selected from the group consisting of alkyl,—O-alkyl, haloalkoxy, methoxy-ethoxy and halogen, heteroaryl, alkyl orcycloalkyl; R₂ is C or N; R₃ is C, N, S or O; R₄ is C, O, S or N; R₅ isC, N or S; R₆ is H, alkyl, halogen, haloalkyl, thioalkyl or absenthydrogen; R₇ is

at least one of R₈ or R₉ is N; and the other is carbon; R₁₀ is —NR₁₁R₁₂;R₁₁ is H, lower alkyl, alkyl ether, alkyl alcohol, acyl or a 5- or6-membered cyclic ring having from 1 to 3 hetero ring atoms selectedfrom the group consisting of S, N and O, unsubstituted or substitutedwith a group selected from the group consisting of −OCH₃, —CH₂OH,—CH₂OCH₃ and —OH; R₁₂ is H or lower alkyl; or a pharmaceuticallyacceptable salt thereof.
 5. The compound according to claim 1, wherein:R₁ is unsubstituted aryl, aryl substituted with a group selected fromthe group consisting of alkyl, —O-alkyl, haloalkoxy, methoxy-ethoxy andhalogen, heteroaryl, alkyl or cycloalkyl; R₂ is C or N; R₃ is C, N, S orO; R₄ is C, O, S or N; R₅ is C, N or S; R₆ is H, alkyl, halogen,haloalkyl, thioalkyl or hydrogen; R₇ is

at least one of R₈ or R₉ is N; and the other is carbon; R₁₀ is —NR₁₁R₁₂,O-alkyl, hydroxy-dimethylethylamino, hydroxyl-methylethylamino,cyclohept-2-ylamino, morpholino, thiomorpholino, oxothiomorpholino,dioxothiomorpholino, alkyl-carbamoyl-alkyl-amino, difluoroazetidine,ethoxyazetidine, azetidin-3-yloxy acetic acid tert-butyl ether,azetidine-3-yloxy acetic acid hydrochloride, or a 4- to 6-memberedcyclic ring having from 1 to 3 hetero ring atoms selected from the groupconsisting of S, N and O, unsubstituted or substituted with a groupselected from the group consisting of amino, amide, —N(CH₃)C(O)CH₃,cyclopropanecarbonyl-methyl, —OCH₃, —OCH₂C(O)OC(CH₃)₃, OCH₂C(O)OH,—CH₂OH, —CH₂OCH₃ and —OH; R₁₁ is H, lower alkyl, alkyl ether,alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl,ethoxymethyl, —CH₂CH₂CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to6-membered cyclic ring having from 1 to 3 hetero ring atoms selectedfrom the group consisting of S, N and O, unsubstituted or substitutedwith a group selected from the group consisting of —OCH₃, —CH₂OH,—CH₂OCH₃, —OCH₂C(O)OC(CH₃)₃, —OCH₂C(O)OH and —OH; R₁₂ is H or loweralkyl; or a pharmaceutically acceptable salt thereof.
 6. The compoundaccording to claim 1, wherein: R₁ is unsubstituted aryl, arylsubstituted with a group selected from the group consisting of alkyl,—O-alkyl, haloalkoxy, methoxy-ethoxy and halogen, heteroaryl, alkyl orcycloalkyl; R₂ is C or N; R₃ is C, N, S or O; R₄ is C, O, S or N; R₅ isC, N or S; R₆ is H, alkyl, halogen, haloalkyl, thioalkyl or hydrogen; R₇is

at least one of R₈ or R₉ is N; and the other is carbon; R₁₀ is —NR₁₁R₁₂,O-alkyl, hydroxy-dimethylethylamino, hydroxyl-methylethylamino,cyclohept-2-ylamino, morpholino, thiomorpholino, oxothiomorpholino,dioxothiomorpholino, alkyl-carbamoyl-alkyl-amino, difluoroazetidine,ethoxyazetidine, azetidin-3-yloxy acetic acid tert-butyl ether,azetidine-3-yloxy acetic acid hydrochloride, or a 4- to 6-memberedcyclic ring having from 1 to 3 hetero ring atoms selected from the groupconsisting of S, N and O, unsubstituted or substituted with a groupselected from the group consisting of amino, amide, —N(CH₃)C(O)CH₃,cyclopropanecarbonyl-methyl, —OCH₃, —OCH₂C(O)OC(CH₃)₃, OCH₂C(O)OH,—CH₂OH, —CH₂OCH₃ and —OH; R₁₁ is H, lower alkyl, alkyl ether,alkyl-aryl, trifluoromethyl, methoxymethyl, cyclopropylmethoxy-ethyl,ethoxymethyl, —CH₂CH₂CN, alkyl alcohol, acyl, cycloalkyl, or a 4- to6-membered cyclic ring having from 1 to 3 hetero ring atoms selectedfrom the group consisting of S, N and O, unsubstituted or substitutedwith a group selected from the group consisting of —OCH₃, —CH₂OH,—CH₂OCH₃, CH₂C(O)OC(CH₃)₃, —OCH₂C(O)OH and —OH; R₁₂ is H or lower alkyl;or a pharmaceutically acceptable salt thereof.
 7. The compound accordingto claim 1, wherein R₆ is —CF₃.
 8. The compound according to claim 1,wherein R₁₀ is —(CH₃)(CH₂)_(n)OCH₃, —N(CH₃)CH₂C(O)OCH₃,—N(CH₃)CH₂C(O)NHCH₃, —N(CH₃)C(O)CH₃, —N(CH₃)(CH₂)_(n)CH₃,—NH(CH₂)_(n)CH₃, —N(CH₂CH₃)(CH₂)_(n)OCH₃, diethylamino,—N(CH₃)C(O)CH₂OCH₃, —N(CH₃)CH(CH₃)CH₂OCH₃, —N(CH₃)(CH₂)_(n)O,—N(CH₂)_(n)O, —NCH₂(CH₃)CH₂O or —N-tetrahydropyran; wherein n is 1, 2 or3.
 9. The compound according to claim 1, wherein said compound is5-phenyl-2-trifluoromethyl-furan-3-carboxylic acid(6-morpholin-4-yl-pyridin-3-yl)-amide, 10-13. (canceled)
 14. Thecompound according to claim 1, wherein said compound is2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid{2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide. 15-20.(canceled)
 21. The compound of claim 1 wherein said compound has theformula

wherein R₁, R₆ and R₁₀ are as above.
 22. The compound of claim 1 whereinsaid compound has the formula

wherein R₁, R₆ and R₁₀ are as above.
 23. The compound of claim 1 whereinsaid compound has the formula:

wherein R₁, R₆ and R₁₀ are as above.